NM_007374.3:c.385G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_007374.3(SIX6):c.385G>A(p.Glu129Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,613,104 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 36 hom. )

Consequence

SIX6
NM_007374.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 10.0

Publications

29 publications found

Variant links:

Genes affected

SIX6 (HGNC:10892): (SIX homeobox 6) The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in eye development. Defects in this gene are a cause of isolated microphthalmia with cataract type 2 (MCOPCT2). [provided by RefSeq, Jul 2008]

SIX6 links:

C14orf39 (HGNC:19849): (chromosome 14 open reading frame 39) Predicted to be involved in gamete generation and meiosis I. Predicted to be located in chromosome. Predicted to be active in central element. Implicated in primary ovarian insufficiency 18 and spermatogenic failure 52. [provided by Alliance of Genome Resources, Apr 2022]

C14orf39 Gene-Disease associations (from GenCC):

premature ovarian failure 18
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
spermatogenic failure 52
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

C14orf39 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.027642071).

BP6

Variant 14-60509783-G-A is Benign according to our data. Variant chr14-60509783-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445796.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00411 (626/152308) while in subpopulation NFE AF = 0.00695 (473/68020). AF 95% confidence interval is 0.00644. There are 1 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 36 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX6	NM_007374.3 link	c.385G>A	p.Glu129Lys	missense_variant	Exon 1 of 2	ENST00000327720.6	NP_031400.2	O95475Q6P051
C14orf39	XM_047431324.1 link	c.-144+5612C>T		intron_variant	Intron 1 of 18		XP_047287280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX6	ENST00000327720.6 link	c.385G>A	p.Glu129Lys	missense_variant	Exon 1 of 2	1	NM_007374.3	ENSP00000328596.5		O95475
C14orf39	ENST00000556799.1 link	c.-144+5612C>T		intron_variant	Intron 1 of 5	4		ENSP00000451441.1		G3V3U9

Frequencies

GnomAD3 genomes

AF:

0.00411

AC:

626

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00695

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00403

AC:

1011

AN:

251016

AF XY:

0.00418

show subpopulations

Gnomad AFR exome

AF:

0.000740

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00407

Gnomad NFE exome

AF:

0.00680

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00575

AC:

8403

AN:

1460796

Hom.:

Cov.:

AF XY:

0.00569

AC XY:

4131

AN XY:

726474

show subpopulations

African (AFR)

AF:

0.000927

AC:

AN:

33444

American (AMR)

AF:

0.00170

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39674

South Asian (SAS)

AF:

0.00173

AC:

149

AN:

86246

European-Finnish (FIN)

AF:

0.00450

AC:

240

AN:

53392

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00677

AC:

7519

AN:

1111136

Other (OTH)

AF:

0.00534

AC:

322

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

469

938

1407

1876

2345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00411

AC:

626

AN:

152308

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

302

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41582

American (AMR)

AF:

0.00307

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00166

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00695

AC:

473

AN:

68020

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00558

Hom.:

Bravo

AF:

0.00370

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00402

AC:

488

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a risk or hypomorphic allele in relation to primary open-angle glaucoma (Carnes et al., 2014; Iglesias et al., 2014; Shah et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24150847, 28499933, 28717659, 29165578, 24875647) -

Anophthalmia/microphthalmia-esophageal atresia syndrome;C4225424:Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Anophthalmia-microphthalmia syndrome

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

SIX6-related disorder

Benign:1

May 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.028

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.1

PhyloP100

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.79

Sift

Uncertain

0.020

Sift4G

Benign

0.064

Polyphen

0.97

Vest4

0.80

MVP

0.89

MPC

2.1

ClinPred

0.077

GERP RS

5.4

Varity_R

0.80

gMVP

0.60

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over