chr14-60511125-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_007374.3(SIX6):c.614T>G(p.Leu205Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00291 in 1,612,752 control chromosomes in the GnomAD database, including 21 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 0.0032 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 17 hom. )

Consequence

SIX6
NM_007374.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.75

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074677467).

BP6

Variant 14-60511125-T-G is Benign according to our data. Variant chr14-60511125-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522355.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00321 (488/152192) while in subpopulation NFE AF = 0.00504 (343/67990). AF 95% confidence interval is 0.0046. There are 4 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX6	NM_007374.3 link	c.614T>G	p.Leu205Arg	missense_variant	Exon 2 of 2	ENST00000327720.6	NP_031400.2	O95475Q6P051
C14orf39	XM_047431324.1 link	c.-144+4270A>C		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.614T>G	p.Leu205Arg	missense_variant	Exon 2 of 2	1	NM_007374.3	ENSP00000328596.5		O95475
C14orf39	ENST00000556799.1 link	c.-144+4270A>C		intron_variant	Intron 1 of 5	4		ENSP00000451441.1		G3V3U9

Frequencies

GnomAD3 genomes

AF:

0.00322

AC:

489

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00504

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00312

AC:

763

AN:

244246

AF XY:

0.00334

show subpopulations

Gnomad AFR exome

AF:

0.000530

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.00191

Gnomad EAS exome

AF:

0.0000552

Gnomad FIN exome

AF:

0.00558

Gnomad NFE exome

AF:

0.00452

Gnomad OTH exome

AF:

0.00382

GnomAD4 exome

AF:

0.00288

AC:

4209

AN:

1460560

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

2158

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33476

American (AMR)

AF:

0.00177

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86232

European-Finnish (FIN)

AF:

0.00592

AC:

310

AN:

52394

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00308

AC:

3429

AN:

1111828

Other (OTH)

AF:

0.00225

AC:

136

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

247

494

740

987

1234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00321

AC:

488

AN:

152192

Hom.:

Cov.:

AF XY:

0.00316

AC XY:

235

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41540

American (AMR)

AF:

0.00242

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00504

AC:

343

AN:

67990

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00370

Hom.:

Bravo

AF:

0.00264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00257

AC:

ExAC

AF:

0.00321

AC:

389

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 17, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28717659, 28499933, 24875647) -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SIX6: BS2 -

Anophthalmia-microphthalmia syndrome

Uncertain:1

Jan 13, 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. -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome

Benign:1

Oct 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.078

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.23

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.0075

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.81

PhyloP100

4.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.060

REVEL

Uncertain

0.30

Sift

Benign

0.33

Sift4G

Benign

0.33

Polyphen

0.0090

Vest4

0.49

MVP

0.75

MPC

1.3

ClinPred

0.0094

GERP RS

4.1

Varity_R

0.26

gMVP

0.53

Mutation Taster

=89/11

polymorphism

(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