rs2074913

Variant names:

• chr5-141618784-G-A
• rs2074913
• NM_005219.5:c.117+14C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005219.5(DIAPH1):​c.117+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,532,352 control chromosomes in the GnomAD database, including 4,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (359 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3738 hom.)
• Consequence: DIAPH1 NM_005219.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.88
• Publications: 7 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

ENSG00000228737 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-141618784-G-A is Benign according to our data. Variant chr5-141618784-G-A is described in ClinVar as Benign. ClinVar VariationId is 45212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.117+14C>T		intron_variant	Intron 1 of 27	ENST00000389054.8	NP_005210.3
DIAPH1	NM_001079812.3	c.117+14C>T		intron_variant	Intron 1 of 26		NP_001073280.1
DIAPH1	NM_001314007.2	c.117+14C>T		intron_variant	Intron 1 of 28		NP_001300936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.117+14C>T		intron_variant	Intron 1 of 27	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.117+14C>T		intron_variant	Intron 1 of 26	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.117+14C>T		intron_variant	Intron 1 of 28			ENSP00000494675.1
DIAPH1	ENST00000523100.5	n.117+14C>T		intron_variant	Intron 1 of 10	5		ENSP00000428208.1

Frequencies

GnomAD3 genomes AF: 0.0576 AC: 8764 AN: 152134 Hom.: 361 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0907

Gnomad EAS AF: 0.0432

Gnomad SAS AF: 0.0500

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0791

Gnomad OTH AF: 0.0755

GnomAD2 exomes AF: 0.0627 AC: 10183 AN: 162482 AF XY: 0.0624

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.0834

Gnomad EAS exome AF: 0.0407

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0647

GnomAD4 exome AF: 0.0691 AC: 95427 AN: 1380102 Hom.: 3738 Cov.: 25 AF XY: 0.0691 AC XY: 47246 AN XY: 683928

African (AFR) AF: 0.0112 AC: 346 AN: 30906

American (AMR) AF: 0.0317 AC: 1178 AN: 37142

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 2048 AN: 24854

East Asian (EAS) AF: 0.0271 AC: 972 AN: 35810

South Asian (SAS) AF: 0.0515 AC: 4046 AN: 78586

European-Finnish (FIN) AF: 0.121 AC: 6010 AN: 49648

Middle Eastern (MID) AF: 0.0764 AC: 423 AN: 5538

European-Non Finnish (NFE) AF: 0.0722 AC: 76521 AN: 1060302

Other (OTH) AF: 0.0677 AC: 3883 AN: 57316

GnomAD4 genome AF: 0.0576 AC: 8767 AN: 152250 Hom.: 359 Cov.: 32 AF XY: 0.0588 AC XY: 4377 AN XY: 74442

African (AFR) AF: 0.0126 AC: 524 AN: 41564

American (AMR) AF: 0.0366 AC: 560 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 315 AN: 3472

East Asian (EAS) AF: 0.0436 AC: 225 AN: 5166

South Asian (SAS) AF: 0.0499 AC: 241 AN: 4834

European-Finnish (FIN) AF: 0.124 AC: 1321 AN: 10614

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0791 AC: 5376 AN: 67978

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

Alfa AF: 0.0710 Hom.: 125

Bravo AF: 0.0477

Asia WGS AF: 0.0860 AC: 297 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jan 25, 2016

Eurofins Ntd Llc (ga)

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

117+14C>T in Intron 01 of DIAPH1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 7.3% (459/6300) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2074913). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 1 Benign:1

Jan 12, 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 11, 2018

GeneDx

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	-0.46
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		1.9
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2074913; hg19: chr5-140998351;