chr5-141528502-A-T

Variant names:

• chr5-141528502-A-T
• rs727504838
• NM_005219.5:c.3099T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005219.5(DIAPH1):​c.3099T>A​(p.Asp1033Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1033N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.690
• Publications: 0 publications found

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]

DIAPH1 Gene-Disease associations (from GenCC):

• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.109059095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.3099T>A	p.Asp1033Glu	missense_variant	Exon 23 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3099T>A	p.Asp1033Glu	missense_variant	Exon 23 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.3072T>A	p.Asp1024Glu	missense_variant	Exon 22 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.3099T>A	p.Asp1033Glu	missense_variant	Exon 23 of 29			ENSP00000494675.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1033 of the DIAPH1 protein (p.Asp1033Glu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Benign	0.076
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.14	T;.;T;.;T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T;T;T;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L;.;.;.;.;.
PhyloP100		-0.69
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	.;.;.;N;N;.
REVEL	Benign	0.083
Sift	Benign	0.59	.;.;.;T;T;.
Sift4G	Benign	0.84	T;.;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.21
MutPred		0.52		Gain of catalytic residue at D1033 (P = 0.0532);Gain of catalytic residue at D1033 (P = 0.0532);.;.;Gain of catalytic residue at D1033 (P = 0.0532);.;
MVP		0.53
MPC		0.60
ClinPred		0.059	T
GERP RS		-3.9
Varity_R		0.041
gMVP		0.080
Mutation Taster		=90/10	polymorphism

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: rs727504838; hg19: chr5-140908069;