rs764739820

Positions:

• chr5-141516969-G-A

Variant summary

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

The NM_005219.5(DIAPH1):​c.3701C>T​(p.Ala1234Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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]

LOC124901091 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13358405).
• BS2: High AC in GnomAdExome4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.3701C>T	p.Ala1234Val	missense_variant	28/28	ENST00000389054.8	NP_005210.3
LOC124901091	XR_007058971.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3701C>T	p.Ala1234Val	missense_variant	28/28	5	NM_005219.5	ENSP00000373706	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249520 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135388

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.0000371 AC XY: 27 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000827 AC: 1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

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. 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 475709). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. This variant is present in population databases (rs764739820, gnomAD 0.009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1234 of the DIAPH1 protein (p.Ala1234Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.080	T;T;.;T;.;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.69	T;T;T;T;.;T;.;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.
MutationTaster	Benign	0.70	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.67	.;.;N;N;.;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.049	.;.;D;D;.;.;.;.
Sift4G	Benign	0.21	T;T;T;T;.;T;.;.
Polyphen		0.0010	B;.;.;.;.;.;.;.
Vest4		0.030
MVP		0.83
MPC		0.56
ClinPred		0.14	T
GERP RS		2.2
Varity_R		0.096
gMVP		0.28

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: rs764739820; hg19: chr5-140896536;