7-107661725-C-G

Variant names:

• chr7-107661725-C-G
• rs539699299
• NM_000441.2:c.84C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_000441.2(SLC26A4):​c.84C>G​(p.Ser28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.699

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79
• PP5: Variant 7-107661725-C-G is Pathogenic according to our data. Variant chr7-107661725-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2018278.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.84C>G	p.Ser28Arg	missense_variant	Exon 2 of 21	ENST00000644269.2	NP_000432.1
SLC26A4-AS1	NR_028137.1	n.74G>C		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.84C>G	p.Ser28Arg	missense_variant	Exon 2 of 21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406212 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 695208

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). A different variant (c.84C>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 11919333, 15679828, 16570074, 16791000, 18310264, 24224479, 29739340). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 28 of the SLC26A4 protein (p.Ser28Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.027	D;.;D
Polyphen		0.92	P;P;.
Vest4		0.91
MutPred		0.75		Gain of MoRF binding (P = 0.014);Gain of MoRF binding (P = 0.014);Gain of MoRF binding (P = 0.014);
MVP		0.96
MPC		0.020
ClinPred		0.96	D
GERP RS		2.4
Varity_R		0.65
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs539699299; hg19: chr7-107302170;