rs763106782

Positions:

• chr5-141526086-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS2_Supporting

The NM_005219.5(DIAPH1):​c.3526C>T​(p.Arg1176Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.79

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.3526C>T	p.Arg1176Trp	missense_variant	26/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3526C>T	p.Arg1176Trp	missense_variant	26/28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.3499C>T	p.Arg1167Trp	missense_variant	25/27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.3526C>T	p.Arg1176Trp	missense_variant	26/29			ENSP00000494675.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461812 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

The p.Arg1176Trp variant in DIAPH1 has not been previously reported in individua ls with hearing loss. This variant has been identified in 1/16512 South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs763106782). Computational prediction tools and conservation analyse s suggest that the p.Arg1176Trp variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, the cli nical significance of the p.Arg1176Trp variant is uncertain. -

Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1176 of the DIAPH1 protein (p.Arg1176Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228576). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;T;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	2.0	M;.;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	.;.;.;D;D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	.;.;.;D;D;.
Sift4G	Uncertain	0.0020	D;.;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.45
MutPred		0.37		Loss of MoRF binding (P = 0.081);Loss of MoRF binding (P = 0.081);.;.;Loss of MoRF binding (P = 0.081);.;
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs763106782; hg19: chr5-140905653;