rs199743522

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005982.4(SIX1):c.474C>T(p.Ala158=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,613,578 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

SIX1
NM_005982.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.162

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:

MIR9718 (HGNC:):

MIR9718 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 14-60648716-G-A is Benign according to our data. Variant chr14-60648716-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 466172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.162 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000723 (11/152196) while in subpopulation NFE AF= 0.000147 (10/68030). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SIX1	NM_005982.4 linkuse as main transcript	c.474C>T	p.Ala158=	synonymous_variant	1/2	ENST00000645694.3
SIX1	XM_017021602.3 linkuse as main transcript	c.474C>T	p.Ala158=	synonymous_variant	1/2
MIR9718	NR_162089.1 linkuse as main transcript			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SIX1	ENST00000645694.3 linkuse as main transcript	c.474C>T	p.Ala158=	synonymous_variant	1/2		NM_005982.4	P1
SIX1	ENST00000554986.2 linkuse as main transcript	c.42-2139C>T		intron_variant		3
SIX1	ENST00000553535.2 linkuse as main transcript	n.249-2139C>T		intron_variant, non_coding_transcript_variant		3
SIX1	ENST00000555955.3 linkuse as main transcript	n.1198-2139C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

251062

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000675

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000907

EpiCase

AF:

0.000327

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Branchiootic syndrome 3;C1854594:Autosomal dominant nonsyndromic hearing loss 23;C4551702:Branchiootorenal syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 15, 2020

- -

SIX1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

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

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.95

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