rs33912345

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
SIX6	NM_007374.3 linkuse as main transcript	c.421C>A	p.His141Asn	missense_variant	1/2	ENST00000327720.6	NP_031400.2	O95475Q6P051
C14orf39	XM_047431324.1 linkuse as main transcript	c.-144+5576G>T		intron_variant			XP_047287280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX6	ENST00000327720.6 linkuse as main transcript	c.421C>A	p.His141Asn	missense_variant	1/2	1	NM_007374.3	ENSP00000328596.5		O95475
C14orf39	ENST00000556799.1 linkuse as main transcript	c.-144+5576G>T		intron_variant		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

GnomAD3 exomes

AF:

0.531

AC:

132666

AN:

249984

Hom.:

39143

AF XY:

0.530

AC XY:

71688

AN XY:

135180

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 SAS exome

AF:

0.429

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

Gnomad4 AFR exome

AF:

0.0962

Gnomad4 AMR exome

AF:

0.671

Gnomad4 ASJ exome

AF:

0.499

Gnomad4 EAS exome

AF:

0.226

Gnomad4 SAS exome

AF:

0.432

Gnomad4 FIN exome

AF:

0.717

Gnomad4 NFE exome

AF:

0.608

Gnomad4 OTH exome

AF:

0.517

GnomAD4 genome

AF:

0.454

AC:

69077

AN:

152080

Hom.:

19710

Cov.:

AF XY:

0.460

AC XY:

34213

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.115

Gnomad4 AMR

AF:

0.594

Gnomad4 ASJ

AF:

0.510

Gnomad4 EAS

AF:

0.229

Gnomad4 SAS

AF:

0.419

Gnomad4 FIN

AF:

0.728

Gnomad4 NFE

AF:

0.604

Gnomad4 OTH

AF:

0.429

Alfa

AF:

0.554

Hom.:

39547

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26365380, 27013732, 24875647, 25537207) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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. -

Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Anophthalmia-microphthalmia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over