7-107689054-T-G

Position:

• chr7-107689054-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.1003T>G​(p.Phe335Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F335L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense, splice_region
• Scores: Splicing: ADA: 0.5876
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.64

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107689054-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 7-107689054-T-G is Pathogenic according to our data. Variant chr7-107689054-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1210160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1003T>G	p.Phe335Val	missense_variant, splice_region_variant	9/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1003T>G	p.Phe335Val	missense_variant, splice_region_variant	9/21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461500 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727062

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 21, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0060	D;.
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.83		Gain of disorder (P = 0.1464);Gain of disorder (P = 0.1464);
MVP		0.99
MPC		0.075
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.15		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: rs111033212; hg19: chr7-107329499;