rs368974927

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_005982.4(SIX1):c.746C>T(p.Pro249Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000092 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SIX1
NM_005982.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4

Conservation

PhyloP100: 4.23

Variant links:

Genes affected

SIX1 (HGNC:10887): (SIX homeobox 1) 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 limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3). [provided by RefSeq, Jul 2008]

SIX1 links:

SIX1 (HGNC:):

SIX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a chain Homeobox protein SIX1 (size 283) in uniprot entity SIX1_HUMAN there are 18 pathogenic changes around while only 5 benign (78%) in NM_005982.4

BP4

Computational evidence support a benign effect (MetaRNN=0.027870625).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX1	NM_005982.4 linkuse as main transcript	c.746C>T	p.Pro249Leu	missense_variant	2/2	ENST00000645694.3	NP_005973.1	Q15475
SIX1	XM_017021602.3 linkuse as main transcript	c.*165C>T		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SIX1	ENST00000645694.3 linkuse as main transcript	c.746C>T	p.Pro249Leu	missense_variant	2/2		NM_005982.4	ENSP00000494686.1	Q15475
SIX1	ENST00000554986.2 linkuse as main transcript	c.227C>T	p.Pro76Leu	missense_variant	2/2	3		ENSP00000452700.2	H0YK85
SIX1	ENST00000553535.2 linkuse as main transcript	n.434C>T		non_coding_transcript_exon_variant	3/3	3
SIX1	ENST00000555955.3 linkuse as main transcript	n.1383C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251256

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000109

AC:

160

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00352

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000398

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 23

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Jan 01, 2025	The c.746C>T:p.(Pro249Leu) is classified pathogenic by Deafness Variation Database based on PMID:21280147, where the first hearing impaired individual was reported. A second affected individual was reported to ClinVar by GeneDx (SCV001786287.1) as likely benign even though it was detected in an affected person. We detected this variant in three additional hearing impaired individuals in a WES study where no other candidates were found. All together, there are 5 affected individuals documented that do not have any other candidates identified in WES, supporting pathogenicity of the variant. This variant is common among Ashkenazi Jews (0.3%) but very rare in other population, suggesting a founder effect in the Ashkenazi population. -

Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 30, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2020

This variant is associated with the following publications: (PMID: 21280147) -

SIX1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

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). -

Branchiootic syndrome 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;T;D

Eigen

Benign

-0.15

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.3

L;.;L

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

N;.;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.012

D;.;.

Sift4G

Benign

0.14

T;D;.

Polyphen

0.0010

B;.;B

Vest4

0.25

MutPred

0.24

Loss of glycosylation at P249 (P = 0.0548);.;Loss of glycosylation at P249 (P = 0.0548);

MVP

0.98

MPC

0.016

ClinPred

0.10

GERP RS

5.2

Varity_R

0.091

gMVP

0.26

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