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. The variant received -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
• Publications: 10 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: Benign. The variant received -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 VariationId is 45215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AD,AR 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

GnomAD2 exomes AF: 0.0254 AC: 6333 AN: 249380 AF XY: 0.0259

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 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

African (AFR) AF: 0.0124 AC: 415 AN: 33472

American (AMR) AF: 0.00698 AC: 312 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00559 AC: 146 AN: 26134

East Asian (EAS) AF: 0.0456 AC: 1811 AN: 39690

South Asian (SAS) AF: 0.0242 AC: 2091 AN: 86242

European-Finnish (FIN) AF: 0.0510 AC: 2725 AN: 53412

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5768

European-Non Finnish (NFE) AF: 0.0264 AC: 29385 AN: 1111364

Other (OTH) AF: 0.0236 AC: 1427 AN: 60388

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

African (AFR) AF: 0.0114 AC: 472 AN: 41490

American (AMR) AF: 0.00962 AC: 147 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.0464 AC: 240 AN: 5168

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4824

European-Finnish (FIN) AF: 0.0509 AC: 538 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0278 AC: 1890 AN: 68004

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.0255 Hom.: 164

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

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		-2.2
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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