7-107661666-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000441.2(SLC26A4):c.25G>A(p.Glu9Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000847 in 1,416,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E9E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17054075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.25G>A	p.Glu9Lys	missense_variant	2/21	ENST00000644269.2
SLC26A4-AS1	NR_028137.1	n.133C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.25G>A	p.Glu9Lys	missense_variant	2/21		NM_000441.2	P1
SLC26A4-AS1	ENST00000668981.1	n.193C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000847 AC: 12 AN: 1416558 Hom.: 0 Cov.: 30 AF XY: 0.0000143 AC XY: 10 AN XY: 701662

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: 0.000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.75	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.64	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.78	N;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.014	D;.;D
Sift4G	Benign	0.52	T;.;T
Polyphen		0.020	B;B;.
Vest4		0.31
MutPred		0.19		Gain of ubiquitination at E9 (P = 0.0069);Gain of ubiquitination at E9 (P = 0.0069);Gain of ubiquitination at E9 (P = 0.0069);
MVP		0.81
MPC		0.012
ClinPred		0.23	T
GERP RS		3.1
Varity_R		0.088
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: rs758648839; hg19: chr7-107302111;