5-141573743-G-C

Position:

• chr5-141573743-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005219.5(DIAPH1):​c.2107C>G​(p.Pro703Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,537,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 7.32

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19405854).
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.2107C>G	p.Pro703Ala	missense_variant	16/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.2107C>G	p.Pro703Ala	missense_variant	16/28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.2080C>G	p.Pro694Ala	missense_variant	15/27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.2107C>G	p.Pro703Ala	missense_variant	16/29			ENSP00000494675.1

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 21 AN: 147096 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000271

Gnomad OTH AF: 0.000504

GnomAD3 exomes AF: 0.000169 AC: 32 AN: 189262 Hom.: 0 AF XY: 0.000219 AC XY: 22 AN XY: 100666

Gnomad AFR exome AF: 0.0000812

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000466

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 184 AN: 1390110 Hom.: 0 Cov.: 37 AF XY: 0.000146 AC XY: 100 AN XY: 685832

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: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.000123

GnomAD4 genome AF: 0.000143 AC: 21 AN: 147096 Hom.: 0 Cov.: 21 AF XY: 0.000154 AC XY: 11 AN XY: 71608

Gnomad4 AFR AF: 0.0000502

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000271

Gnomad4 OTH AF: 0.000504

Alfa AF: 0.000285 Hom.: 0

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 21, 2015

The p.Pro703Ala variant has not been previously reported in individuals with hea ring loss, but has been identified in 14/32612 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201433617 ). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impac t to the protein. In summary, the clinical significance of the p.Pro703Ala varia nt 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

Jan 14, 2024

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 703 of the DIAPH1 protein (p.Pro703Ala). This variant is present in population databases (rs201433617, gnomAD 0.03%). 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: 228575). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.29	T;.;T;.;T;.
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T;T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;.;.;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.12	T;.;.;T;T;T
Sift4G	Uncertain	0.0080	D;.;D;D;D;D
Polyphen		0.0030	B;.;.;.;.;.
Vest4		0.46
MutPred		0.61		Loss of glycosylation at P703 (P = 0.0025);Loss of glycosylation at P703 (P = 0.0025);.;.;Loss of glycosylation at P703 (P = 0.0025);.;
MVP		0.78
MPC		0.11
ClinPred		0.11	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.033
gMVP		0.12

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: rs201433617; hg19: chr5-140953310;