rs111033191

Positions:

• chr7-107698089-A-C
• chr7-107698089-A-G

Variant summary

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

The NM_000441.2(SLC26A4):​c.1592A>C​(p.Lys531Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 272) in uniprot entity S26A4_HUMAN there are 26 pathogenic changes around while only 8 benign (76%) 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.1592A>C	p.Lys531Thr	missense_variant	14/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1592A>C	p.Lys531Thr	missense_variant	14/21		NM_000441.2	ENSP00000494017	P1
SLC26A4	ENST00000477350.5	n.439A>C		non_coding_transcript_exon_variant	4/5	4
SLC26A4	ENST00000480841.5	n.441A>C		non_coding_transcript_exon_variant	5/8	3
SLC26A4	ENST00000644846.1	c.305A>C	p.Lys102Thr	missense_variant, NMD_transcript_variant	4/10			ENSP00000494344

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 08, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Lys531Thr variant in SLC26A4 has been previously reported by our laboratory in one indivi dual with hearing loss and EVA, who also has another reported pathogenic variant in SLC26A4 in trans. This variant has not been identified in large population s tudies. Computational prediction tools and conservation analyses suggest that th e p.Lys531Thr variant may impact the protein, though this information is not pre dictive enough to determine pathogenicity. However, the presence of this variant in trans with a reported pathogenic variant in SLC26A4 in an individual with he aring loss and EVA, the extremely low allele frequency in the general population , and computational predictions increase the likelihood that the p.Lys531Thr var iant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Lys531Thr variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.3	D;.
REVEL	Uncertain	0.64
Sift	Benign	0.089	T;.
Sift4G	Benign	0.10	T;.
Polyphen		0.82	P;P
Vest4		0.63
MutPred		0.48		Loss of ubiquitination at K531 (P = 0.0134);Loss of ubiquitination at K531 (P = 0.0134);
MVP		0.97
MPC		0.046
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.77
gMVP		0.70

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: rs111033191; hg19: chr7-107338534;