rs539699299

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-107661725-C-A
• chr7-107661725-C-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS1 PM1 PM5 PP2 PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.84C>A​(p.Ser28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000577 in 1,558,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S28G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.699
• Publications: 12 publications found

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

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS1: Transcript NM_000441.2 (SLC26A4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000441.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107661723-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 446459.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.
• PP5: Variant 7-107661725-C-A is Pathogenic according to our data. Variant chr7-107661725-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.84C>A	p.Ser28Arg	missense	Exon 2 of 21	NP_000432.1	O43511-1
	SLC26A4-AS1	NR_028137.1		n.74G>T		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.84C>A	p.Ser28Arg	missense	Exon 2 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.84C>A	p.Ser28Arg	missense	Exon 1 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.84C>A	p.Ser28Arg	missense	Exon 2 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000613 AC: 1 AN: 163060 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000795

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000427 AC: 6 AN: 1406212 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 2 AN XY: 695208

African (AFR) AF: 0.00 AC: 0 AN: 32384

American (AMR) AF: 0.00 AC: 0 AN: 37592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37136

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1087284

Other (OTH) AF: 0.00 AC: 0 AN: 58570

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal recessive nonsyndromic hearing loss 4 (3)
3	-	-	not provided (3)
3	-	-	Pendred syndrome (3)
1	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.70
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.027	D
Polyphen		0.92	P
Vest4		0.91
MutPred		0.75		Gain of MoRF binding (P = 0.014)
MVP		0.96
MPC		0.020
ClinPred		0.93	D
GERP RS		2.4
Varity_R		0.65
gMVP		0.76
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs539699299; hg19: chr7-107302170;