rs2302102

Variant names:

• chr5-141524225-G-A
• rs2302102
• NM_005219.5:c.3579C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-141524225-G-A
• chr5-141524225-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005219.5(DIAPH1):​c.3579C>T​(p.Gly1193Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,613,320 control chromosomes in the GnomAD database, including 719 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (52 hom., cov: 31)
  • Exomes 𝑓: 0.026 (667 hom.)
• Consequence: DIAPH1 NM_005219.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.21

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-141524225-G-A is Benign according to our data. Variant chr5-141524225-G-A is described in ClinVar as [Benign]. Clinvar id is 45215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-141524225-G-A is described in Lovd as [Benign]. Variant chr5-141524225-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.023 (3504/152128) while in subpopulation EAS AF= 0.0464 (240/5168). AF 95% confidence interval is 0.0416. There are 52 homozygotes in gnomad4. There are 1785 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3504 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.3579C>T	p.Gly1193Gly	synonymous_variant	Exon 27 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3579C>T	p.Gly1193Gly	synonymous_variant	Exon 27 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.3552C>T	p.Gly1184Gly	synonymous_variant	Exon 26 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.3579C>T	p.Gly1193Gly	synonymous_variant	Exon 27 of 29			ENSP00000494675.1
DIAPH1	ENST00000468119.3	c.-16C>T		5_prime_UTR_variant	Exon 2 of 3	4		ENSP00000493546.1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3503 AN: 152010 Hom.: 52 Cov.: 31

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0278

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0254 AC: 6333 AN: 249380 Hom.: 126 AF XY: 0.0259 AC XY: 3504 AN XY: 135294

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.00684

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.0446

Gnomad SAS exome AF: 0.0251

Gnomad FIN exome AF: 0.0506

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0263 AC: 38359 AN: 1461192 Hom.: 667 Cov.: 30 AF XY: 0.0262 AC XY: 19034 AN XY: 726928

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.00559

Gnomad4 EAS exome AF: 0.0456

Gnomad4 SAS exome AF: 0.0242

Gnomad4 FIN exome AF: 0.0510

Gnomad4 NFE exome AF: 0.0264

Gnomad4 OTH exome AF: 0.0236

GnomAD4 genome AF: 0.0230 AC: 3504 AN: 152128 Hom.: 52 Cov.: 31 AF XY: 0.0240 AC XY: 1785 AN XY: 74380

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.00962

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0464

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0509

Gnomad4 NFE AF: 0.0278

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0241 Hom.: 65

Bravo AF: 0.0192

Asia WGS AF: 0.0480 AC: 166 AN: 3478

EpiCase AF: 0.0222

EpiControl AF: 0.0232

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gly1193Gly in Exon 27 of DIAPH1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 2.3% (160/6862) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2302102). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal dominant nonsyndromic hearing loss 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Jul 01, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.7
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2302102; hg19: chr5-140903792; COSMIC: COSV53880169; COSMIC: COSV53880169;