7-107698089-A-G

Position:

• chr7-107698089-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000441.2(SLC26A4):​c.1592A>G​(p.Lys531Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,042 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.26746714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1592A>G	p.Lys531Arg	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>G	p.Lys531Arg	missense_variant	14/21		NM_000441.2	ENSP00000494017	P1
SLC26A4	ENST00000477350.5	n.439A>G		non_coding_transcript_exon_variant	4/5	4
SLC26A4	ENST00000480841.5	n.441A>G		non_coding_transcript_exon_variant	5/8	3
SLC26A4	ENST00000644846.1	c.305A>G	p.Lys102Arg	missense_variant, NMD_transcript_variant	4/10			ENSP00000494344

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457042 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725250

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	-0.055	N;N
MutationTaster	Benign	0.83	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.87	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.16	T;.
Sift4G	Benign	0.72	T;.
Polyphen		0.0020	B;B
Vest4		0.42
MutPred		0.42		Loss of ubiquitination at K531 (P = 0.0134);Loss of ubiquitination at K531 (P = 0.0134);
MVP		0.87
MPC		0.011
ClinPred		0.84	D
GERP RS		6.0
Varity_R		0.23
gMVP		0.52

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;