rs36039758

Variant names:

• chr7-107683506-A-T
• rs36039758
• NM_000441.2:c.970A>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000441.2(SLC26A4):​c.970A>T​(p.Asn324Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0018 in 1,613,876 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (24 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 4.50
• Publications: 16 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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000441.2
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0110755265).
• BP6: Variant 7-107683506-A-T is Benign according to our data. Variant chr7-107683506-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00972 (1480/152298) while in subpopulation AFR AF = 0.0341 (1418/41558). AF 95% confidence interval is 0.0326. There are 24 homozygotes in GnomAd4. There are 719 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,AD gene

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.970A>T	p.Asn324Tyr	missense	Exon 8 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.970A>T	p.Asn324Tyr	missense	Exon 8 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.970A>T	p.Asn324Tyr	missense	Exon 7 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.970A>T	p.Asn324Tyr	missense	Exon 8 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.00970 AC: 1476 AN: 152180 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00243 AC: 610 AN: 250854 AF XY: 0.00198

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000978 AC: 1430 AN: 1461578 Hom.: 24 Cov.: 31 AF XY: 0.000828 AC XY: 602 AN XY: 727082

African (AFR) AF: 0.0353 AC: 1182 AN: 33462

American (AMR) AF: 0.00103 AC: 46 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.0000791 AC: 88 AN: 1111824

Other (OTH) AF: 0.00162 AC: 98 AN: 60376

GnomAD4 genome AF: 0.00972 AC: 1480 AN: 152298 Hom.: 24 Cov.: 32 AF XY: 0.00965 AC XY: 719 AN XY: 74472

African (AFR) AF: 0.0341 AC: 1418 AN: 41558

American (AMR) AF: 0.00255 AC: 39 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68010

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00144 Hom.: 3

Bravo AF: 0.0111

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00310 AC: 376

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	3	Pendred syndrome (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 4 (2)
-	-	1	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.99
MPC		0.075
ClinPred		0.043	T
GERP RS		4.5
Varity_R		0.71
gMVP		0.87
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs36039758; hg19: chr7-107323951; COSMIC: COSV55916364;