rs200735096

Variant names:

• chr5-141573865-C-T
• rs200735096
• NM_005219.5:c.1985G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005219.5(DIAPH1):​c.1985G>A​(p.Gly662Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,532,482 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 25)
  • Exomes 𝑓: 0.0015 (11 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.22

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042927265).
• BP6: Variant 5-141573865-C-T is Benign according to our data. Variant chr5-141573865-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00153 (2118/1383332) while in subpopulation NFE AF= 0.0013 (1392/1071118). AF 95% confidence interval is 0.00124. There are 11 homozygotes in gnomad4_exome. There are 1037 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 292 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.1985G>A	p.Gly662Asp	missense_variant	Exon 16 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.1985G>A	p.Gly662Asp	missense_variant	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.1958G>A	p.Gly653Asp	missense_variant	Exon 15 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.1985G>A	p.Gly662Asp	missense_variant	Exon 16 of 29			ENSP00000494675.1
DIAPH1	ENST00000647330.1	n.*1212G>A		downstream_gene_variant				ENSP00000494308.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 293 AN: 149038 Hom.: 4 Cov.: 25

Gnomad AFR AF: 0.000273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000853

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00195

GnomAD3 exomes AF: 0.00185 AC: 262 AN: 141466 Hom.: 5 AF XY: 0.00170 AC XY: 124 AN XY: 73060

Gnomad AFR exome AF: 0.000236

Gnomad AMR exome AF: 0.000501

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000981

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.00153 AC: 2118 AN: 1383332 Hom.: 11 Cov.: 37 AF XY: 0.00153 AC XY: 1037 AN XY: 679516

Gnomad4 AFR exome AF: 0.000219

Gnomad4 AMR exome AF: 0.000429

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00196 AC: 292 AN: 149150 Hom.: 4 Cov.: 25 AF XY: 0.00281 AC XY: 204 AN XY: 72622

Gnomad4 AFR AF: 0.000272

Gnomad4 AMR AF: 0.000268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000855

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00193

Alfa AF: 0.00112 Hom.: 1

Bravo AF: 0.000638

ESP6500AA AF: 0.000505 AC: 2

ESP6500EA AF: 0.000973 AC: 8

ExAC AF: 0.000944 AC: 106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DIAPH1: BP4, BS2 -

Jan 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

May 02, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly662Asp variant in DIAPH1 is classified as benign because it has been identified in 1.2% (214/17174) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Autosomal dominant nonsyndromic hearing loss 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Jan 30, 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
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.0060
DANN	Benign	0.65
DEOGEN2	Benign	0.11	T;.;T;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.31	T;T;T;T;T;T
MetaRNN	Benign	0.0043	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.91	N;.;.;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.25	T;.;.;T;T;T
Sift4G	Benign	0.21	T;.;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.081
MVP		0.37
MPC		0.15
ClinPred		0.0043	T
GERP RS		-6.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200735096; hg19: chr5-140953432;