rs146348818

Variant names:

• chr7-107683285-G-C
• rs146348818
• NM_000441.2:c.849G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS2

The NM_000441.2(SLC26A4):​c.849G>C​(p.Met283Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,613,354 control chromosomes in the GnomAD database, including 8 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 (★★). The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (5 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.52
• Publications: 5 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 -13 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, 6 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 hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009616643).
• BP6: Variant 7-107683285-G-C is Benign according to our data. Variant chr7-107683285-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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.849G>C	p.Met283Ile	missense	Exon 7 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.849G>C	p.Met283Ile	missense	Exon 7 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.849G>C	p.Met283Ile	missense	Exon 6 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.849G>C	p.Met283Ile	missense	Exon 7 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152122 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00937

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000729 AC: 183 AN: 251186 AF XY: 0.000508

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000357 AC: 521 AN: 1461114 Hom.: 5 Cov.: 31 AF XY: 0.000322 AC XY: 234 AN XY: 726910

African (AFR) AF: 0.00974 AC: 326 AN: 33454

American (AMR) AF: 0.000626 AC: 28 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00107 AC: 6 AN: 5582

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1111558

Other (OTH) AF: 0.000712 AC: 43 AN: 60362

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152240 Hom.: 3 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74444

African (AFR) AF: 0.00936 AC: 389 AN: 41544

American (AMR) AF: 0.000786 AC: 12 AN: 15266

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68004

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000435 Hom.: 0

Bravo AF: 0.00292

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Pendred syndrome (2)
-	-	1	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	-0.24	N
PhyloP100		2.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.39
Sift	Benign	0.44	T
Sift4G	Benign	1.0	T
Polyphen		0.013	B
Vest4		0.69
MutPred		0.81		Gain of sheet (P = 0.1208)
MVP		0.92
MPC		0.018
ClinPred		0.0066	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.84
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs146348818; hg19: chr7-107323730;