14-60645516-TAA-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005982.4(SIX1):c.*765_*766del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: SIX1 NM_005982.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.09

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00116 (172/147706) while in subpopulation SAS AF= 0.00192 (9/4692). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX1	NM_005982.4	c.*765_*766del		3_prime_UTR_variant	2/2	ENST00000645694.3
SIX1	XM_017021602.3	c.*1039_*1040del		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX1	ENST00000645694.3	c.*765_*766del		3_prime_UTR_variant	2/2		NM_005982.4	P1
SIX1	ENST00000554986.2	c.*765_*766del		3_prime_UTR_variant	2/2	3
SIX1	ENST00000553535.2	n.1308_1309del		non_coding_transcript_exon_variant	3/3	3
SIX1	ENST00000555955.3	n.2257_2258del		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 172 AN: 147658 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000673

Gnomad ASJ AF: 0.000873

Gnomad EAS AF: 0.000592

Gnomad SAS AF: 0.00191

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00199

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00116 AC: 172 AN: 147706 Hom.: 0 Cov.: 0 AF XY: 0.00104 AC XY: 75 AN XY: 71868

Gnomad4 AFR AF: 0.000320

Gnomad4 AMR AF: 0.000673

Gnomad4 ASJ AF: 0.000873

Gnomad4 EAS AF: 0.000594

Gnomad4 SAS AF: 0.00192

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.00197

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nonsyndromic Hearing Loss, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Branchiootorenal Spectrum Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs33943216; hg19: chr14-61112234;