7-107661728-G-C

Variant names:

• chr7-107661728-G-C
• rs1554352240
• NM_000441.2:c.87G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP5_Moderate

The NM_000441.2(SLC26A4):​c.87G>C​(p.Glu29Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E29G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.78
• Publications: 2 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 11 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107661727-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552271.
• 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 7-107661728-G-C is Pathogenic according to our data. Variant chr7-107661728-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1065202.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.87G>C	p.Glu29Asp	missense	Exon 2 of 21	NP_000432.1
	SLC26A4-AS1	NR_028137.1		n.71C>G		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.87G>C	p.Glu29Asp	missense	Exon 2 of 21	ENSP00000494017.1
	SLC26A4	ENST00000440056.1	TSL:4	c.87G>C	p.Glu29Asp	missense	Exon 2 of 4	ENSP00000394760.1
	SLC26A4-AS1	ENST00000440512.4	TSL:3	n.276C>G		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Precision Medicine Center, Zhengzhou University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2: not found in gnomAD PM3: Pathogenic mutation confirmed in trans in one patient PM5: Another pathogenic missense variant(c.85G>C, p.Glu29Gln) at the same codon PP4: Patient phenotype highly specific for gene

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.60
Sift	Benign	0.10	T
Sift4G	Benign	0.068	T
Polyphen		0.026	B
Vest4		0.76
MutPred		0.75		Loss of helix (P = 0.079)
MVP		0.91
MPC		0.012
ClinPred		0.53	D
GERP RS		2.3
Varity_R		0.16
gMVP		0.69
Mutation Taster		=27/73	disease causing

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: rs1554352240; hg19: chr7-107302173;