7-107661643-T-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000441.2(SLC26A4):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.90

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

SLC26A4-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000441.2 (SLC26A4) was described as [Pathogenic] in ClinVar as 1185667
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107661643-T-G is Pathogenic according to our data. Variant chr7-107661643-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2136582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.2T>G	p.Met1?	start_lost	2/21	ENST00000644269.2
SLC26A4-AS1	NR_028137.1	n.156A>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2T>G	p.Met1?	start_lost	2/21		NM_000441.2	P1
SLC26A4-AS1	ENST00000668981.1	n.216A>C		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000579 AC: 1 AN: 172798 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 94532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000738

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410366 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 698144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000260 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 22, 2023	ClinVar contains an entry for this variant (Variation ID: 2136582). Disruption of the initiator codon has been observed in individuals with SLC26A4-related conditions (PMID: 17876604, 19204907, 21961810, 27997596). This variant is present in population databases (rs111033302, gnomAD 0.008%). This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects SLC26A4 function (PMID: 19204907). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	0.99	D
PROVEAN	Benign	-1.1	N;.;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		0.0	B;B;.
Vest4		0.90
MutPred		0.98		Gain of methylation at M1 (P = 0.0082);Gain of methylation at M1 (P = 0.0082);Gain of methylation at M1 (P = 0.0082);
MVP		0.92
ClinPred		0.93	D
GERP RS		3.8
Varity_R		0.89
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs111033302; hg19: chr7-107302088; COSMIC: COSV55916531;