rs17154353

Variant names:

• chr7-107710182-G-A
• rs17154353
• NM_000441.2:c.2218G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-107710182-G-A
• chr7-107710182-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000441.2(SLC26A4):​c.2218G>A​(p.Gly740Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00273 in 1,604,892 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G740V) has been classified as Likely pathogenic. The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.014 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 5.59
• Publications: 17 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

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107710183-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43545.
• 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 hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029495358).
• BP6: Variant 7-107710182-G-A is Benign according to our data. Variant chr7-107710182-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43544.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 = 0.0143 (2182/152248) while in subpopulation AFR AF = 0.0497 (2066/41528). AF 95% confidence interval is 0.048. There are 40 homozygotes in GnomAd4. There are 1041 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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.2218G>A	p.Gly740Ser	missense	Exon 19 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.2218G>A	p.Gly740Ser	missense	Exon 19 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.2218G>A	p.Gly740Ser	missense	Exon 18 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.2140G>A	p.Gly714Ser	missense	Exon 18 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2182 AN: 152130 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

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: 0.000323

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00369 AC: 928 AN: 251264 AF XY: 0.00281

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00151 AC: 2194 AN: 1452644 Hom.: 43 Cov.: 27 AF XY: 0.00129 AC XY: 932 AN XY: 723258

African (AFR) AF: 0.0495 AC: 1643 AN: 33164

American (AMR) AF: 0.00217 AC: 97 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5754

European-Non Finnish (NFE) AF: 0.000175 AC: 193 AN: 1103800

Other (OTH) AF: 0.00373 AC: 224 AN: 60074

GnomAD4 genome AF: 0.0143 AC: 2182 AN: 152248 Hom.: 40 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74456

African (AFR) AF: 0.0497 AC: 2066 AN: 41528

American (AMR) AF: 0.00477 AC: 73 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68014

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00509 Hom.: 41

Bravo AF: 0.0165

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0502 AC: 221

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00437 AC: 530

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	3	Pendred syndrome (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 4 (1)
-	-	1	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.70	N
REVEL	Uncertain	0.40
Sift	Benign	0.091	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.33
MVP		0.98
MPC		0.011
ClinPred		0.023	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.60
Mutation Taster		=92/8	polymorphism

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: rs17154353; hg19: chr7-107350627;