rs1434359940

chr7-107675009-G-Cchr7-107675009-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000441.2(SLC26A4):c.665G>C(p.Gly222Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G222C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.43

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity S26A4_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chr7-107675009-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2735065.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.665G>C	p.Gly222Ala	missense_variant	6/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.665G>C	p.Gly222Ala	missense_variant	6/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pendred syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 24, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.88
Sift	Benign	0.031	D;.
Sift4G	Uncertain	0.036	D;.
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.95		Gain of glycosylation at T225 (P = 0.1401);Gain of glycosylation at T225 (P = 0.1401);
MVP		1.0
MPC		0.076
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.78
gMVP		0.94

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: rs1434359940; hg19: chr7-107315454;