14-60509819-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007374.3(SIX6):c.421C>A(p.His141Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,612,972 control chromosomes in the GnomAD database, including 270,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 19710 hom., cov: 32)

Exomes 𝑓: 0.57 ( 250993 hom. )

Consequence

SIX6
NM_007374.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.21

Publications

101 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.372838E-6).

BP6

Variant 14-60509819-C-A is Benign according to our data. Variant chr14-60509819-C-A is described in ClinVar as Benign. ClinVar VariationId is 260163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX6	NM_007374.3 link	c.421C>A	p.His141Asn	missense_variant	Exon 1 of 2	ENST00000327720.6	NP_031400.2	O95475Q6P051
C14orf39	XM_047431324.1 link	c.-144+5576G>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.421C>A	p.His141Asn	missense_variant	Exon 1 of 2	1	NM_007374.3	ENSP00000328596.5		O95475
C14orf39	ENST00000556799.1 link	c.-144+5576G>T		intron_variant	Intron 1 of 5	4		ENSP00000451441.1		G3V3U9

Frequencies

GnomAD3 genomes

AF:

0.454

AC:

69053

AN:

151962

Hom.:

19703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.558

Gnomad AMR

AF:

0.593

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.228

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.728

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.604

Gnomad OTH

AF:

0.431

GnomAD2 exomes

AF:

0.531

AC:

132666

AN:

249984

AF XY:

0.530

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.682

Gnomad ASJ exome

AF:

0.506

Gnomad EAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.724

Gnomad NFE exome

AF:

0.589

Gnomad OTH exome

AF:

0.540

GnomAD4 exome

AF:

0.575

AC:

839544

AN:

1460892

Hom.:

250993

Cov.:

AF XY:

0.571

AC XY:

414937

AN XY:

726586

show subpopulations

African (AFR)

AF:

0.0962

AC:

3221

AN:

33470

American (AMR)

AF:

0.671

AC:

29942

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

13031

AN:

26130

East Asian (EAS)

AF:

0.226

AC:

8951

AN:

39666

South Asian (SAS)

AF:

0.432

AC:

37227

AN:

86218

European-Finnish (FIN)

AF:

0.717

AC:

38279

AN:

53366

Middle Eastern (MID)

AF:

0.398

AC:

2298

AN:

5768

European-Non Finnish (NFE)

AF:

0.608

AC:

675390

AN:

1111316

Other (OTH)

AF:

0.517

AC:

31205

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

20525

41050

61575

82100

102625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17962

35924

53886

71848

89810

<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:

0.454

AC:

69077

AN:

152080

Hom.:

19710

Cov.:

AF XY:

0.460

AC XY:

34213

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.115

AC:

4793

AN:

41534

American (AMR)

AF:

0.594

AC:

9065

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.510

AC:

1764

AN:

3462

East Asian (EAS)

AF:

0.229

AC:

1180

AN:

5160

South Asian (SAS)

AF:

0.419

AC:

2019

AN:

4816

European-Finnish (FIN)

AF:

0.728

AC:

7698

AN:

10568

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.604

AC:

41040

AN:

67962

Other (OTH)

AF:

0.429

AC:

903

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1557

3115

4672

6230

7787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.525

Hom.:

58311

Bravo

AF:

0.430

TwinsUK

AF:

0.583

AC:

2160

ALSPAC

AF:

0.609

AC:

2347

ESP6500AA

AF:

0.117

AC:

514

ESP6500EA

AF:

0.599

AC:

5151

ExAC

AF:

0.514

AC:

62376

Asia WGS

AF:

0.323

AC:

1126

AN:

3478

EpiCase

AF:

0.576

EpiControl

AF:

0.563

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26365380, 27013732, 24875647, 25537207) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Anophthalmia-microphthalmia syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.30

Eigen

Benign

-0.27

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0000054

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.5

PhyloP100

3.2

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

1.0

REVEL

Uncertain

0.45

Sift

Benign

0.55

Sift4G

Benign

0.93

Polyphen

0.0

Vest4

0.14

MPC

0.96

ClinPred

0.023

GERP RS

5.4

Varity_R

0.25

gMVP

0.54

Mutation Taster

=88/12

polymorphism (auto)

(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