rs200004048

chr5-141576788-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005219.5(DIAPH1):c.1364G>A(p.Arg455Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,528 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R455W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.13

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3587597).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5	c.1364G>A	p.Arg455Gln	missense_variant	13/28	ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.1364G>A	p.Arg455Gln	missense_variant	13/28	5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.1337G>A	p.Arg446Gln	missense_variant	12/27	5		P4
DIAPH1	ENST00000647433.1	c.1364G>A	p.Arg455Gln	missense_variant	13/29			A2
DIAPH1	ENST00000647330.1	c.*591G>A		3_prime_UTR_variant, NMD_transcript_variant	12/15

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000521 AC: 13 AN: 249542 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000795

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461474 Hom.: 0 Cov.: 30 AF XY: 0.0000316 AC XY: 23 AN XY: 727078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000579 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Nov 17, 2014

The p.Arg455Gln variant in DIAPH1 has not been previously reported in individual s with hearing loss, but has been identified in 0.1% (1/1324) by ClinSeq project (dbSNP rs200004048). Although this variant has been seen in the general populat ion, its frequency is not high enough to rule out a pathogenic role. Computation al prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of th e p.Arg455Gln variant is uncertain. -

DIAPH1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2023

The DIAPH1 c.1364G>A variant is predicted to result in the amino acid substitution p.Arg455Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-140956355-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Invitae

Jan 12, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 455 of the DIAPH1 protein (p.Arg455Gln). This variant is present in population databases (rs200004048, gnomAD 0.006%). 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: 163074). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.;D;.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Uncertain	-0.047	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D;.;.;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.056	T;.;.;T;T;T
Sift4G	Uncertain	0.057	T;.;D;T;T;T
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.29
MutPred		0.44		Gain of ubiquitination at K453 (P = 0.0716);Gain of ubiquitination at K453 (P = 0.0716);.;.;Gain of ubiquitination at K453 (P = 0.0716);.;
MVP		0.87
MPC		0.13
ClinPred		0.48	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.20
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: rs200004048; hg19: chr5-140956355; COSMIC: COSV53889256; COSMIC: COSV53889256;