7-107701928-G-C

Position:

• chr7-107701928-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000441.2(SLC26A4):​c.1905G>C​(p.Glu635Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,174 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1905G>C	p.Glu635Asp	missense_variant	17/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1905G>C	p.Glu635Asp	missense_variant	17/21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.192G>C		non_coding_transcript_exon_variant	2/6	5
SLC26A4	ENST00000644846.1	n.615G>C		non_coding_transcript_exon_variant	7/10			ENSP00000494344.1
SLC26A4	ENST00000480841.5	n.*44G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.85	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.42
Sift	Benign	0.42	T;.
Sift4G	Benign	0.25	T;.
Polyphen		0.99	D;D
Vest4		0.43
MutPred		0.27		Loss of methylation at K632 (P = 0.1014);Loss of methylation at K632 (P = 0.1014);
MVP		0.98
MPC		0.074
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.49

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: rs541538556; hg19: chr7-107342373;