7-107702038-G-C

Variant names:

• chr7-107702038-G-C
• rs111033309
• NM_000441.2:c.2015G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000441.2(SLC26A4):​c.2015G>C​(p.Gly672Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G672E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain STAS (size 194) in uniprot entity S26A4_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107702038-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.41882205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2015G>C	p.Gly672Ala	missense_variant	Exon 17 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2015G>C	p.Gly672Ala	missense_variant	Exon 17 of 21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 6	5
SLC26A4	ENST00000644846.1	n.725G>C		non_coding_transcript_exon_variant	Exon 7 of 10			ENSP00000494344.1
SLC26A4	ENST00000480841.5	n.*154G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251180 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457602 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.28
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	-0.52	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.12	N;.
REVEL	Uncertain	0.36
Sift	Benign	0.64	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0020	B;B
Vest4		0.20
MutPred		0.87		Gain of MoRF binding (P = 0.1454);Gain of MoRF binding (P = 0.1454);
MVP		0.91
MPC		0.011
ClinPred		0.21	T
GERP RS		4.7
Varity_R		0.13
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: rs111033309; hg19: chr7-107342483;