14-60645949-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005982.4(SIX1):c.*334C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 174,066 control chromosomes in the GnomAD database, including 62,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.83 (53500 hom., cov: 30)
  • Exomes 𝑓: 0.88 (8974 hom.)
• Consequence: SIX1 NM_005982.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.22

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-60645949-G-C is Benign according to our data. Variant chr14-60645949-G-C is described in ClinVar as [Benign]. Clinvar id is 313459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX1	NM_005982.4	c.*334C>G		3_prime_UTR_variant	2/2	ENST00000645694.3
SIX1	XM_017021602.3	c.*608C>G		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX1	ENST00000645694.3	c.*334C>G		3_prime_UTR_variant	2/2		NM_005982.4	P1
SIX1	ENST00000554986.2	c.*334C>G		3_prime_UTR_variant	2/2	3
SIX1	ENST00000553535.2	n.877C>G		non_coding_transcript_exon_variant	3/3	3
SIX1	ENST00000555955.3	n.1826C>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.833 AC: 125937 AN: 151258 Hom.: 53480 Cov.: 30

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.915

Gnomad AMR AF: 0.884

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.831

GnomAD4 exome AF: 0.877 AC: 19918 AN: 22704 Hom.: 8974 Cov.: 1 AF XY: 0.879 AC XY: 10263 AN XY: 11670

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.913

Gnomad4 ASJ exome AF: 0.894

Gnomad4 EAS exome AF: 0.803

Gnomad4 SAS exome AF: 0.665

Gnomad4 FIN exome AF: 0.954

Gnomad4 NFE exome AF: 0.903

Gnomad4 OTH exome AF: 0.856

GnomAD4 genome AF: 0.832 AC: 125995 AN: 151362 Hom.: 53500 Cov.: 30 AF XY: 0.834 AC XY: 61658 AN XY: 73932

Gnomad4 AFR AF: 0.656

Gnomad4 AMR AF: 0.885

Gnomad4 ASJ AF: 0.882

Gnomad4 EAS AF: 0.849

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.969

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.832

Alfa AF: 0.873 Hom.: 7285

Bravo AF: 0.822

Asia WGS AF: 0.783 AC: 2725 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 23 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. -

Branchiootic syndrome 3 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
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.028
Dann	Benign	0.61

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: rs10144415; hg19: chr14-61112667;