5-141527619-A-C

Position:

• chr5-141527619-A-C

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.3227T>G​(p.Phe1076Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,612,698 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 30)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.25

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=0.009181917).
• BP6: Variant 5-141527619-A-C is Benign according to our data. Variant chr5-141527619-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 226565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00326 (495/151612) while in subpopulation AFR AF= 0.0111 (458/41250). AF 95% confidence interval is 0.0103. There are 4 homozygotes in gnomad4. There are 244 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 495 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.3227T>G	p.Phe1076Cys	missense_variant	24/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3227T>G	p.Phe1076Cys	missense_variant	24/28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.3200T>G	p.Phe1067Cys	missense_variant	23/27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.3227T>G	p.Phe1076Cys	missense_variant	24/29			ENSP00000494675.1

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 493 AN: 151502 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000987

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000898 AC: 224 AN: 249348 Hom.: 1 AF XY: 0.000710 AC XY: 96 AN XY: 135288

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000510 AC: 745 AN: 1461086 Hom.: 7 Cov.: 34 AF XY: 0.000477 AC XY: 347 AN XY: 726824

Gnomad4 AFR exome AF: 0.0156

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000819

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00326 AC: 495 AN: 151612 Hom.: 4 Cov.: 30 AF XY: 0.00329 AC XY: 244 AN XY: 74082

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.000985

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000236

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000814 Hom.: 2

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0101 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2019	This variant is associated with the following publications: (PMID: 30819905) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DIAPH1: BS1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Phe1076Cys in Exon 24 of DIAPH1: This variant is not expected to have clinical s ignificance because it has been identified in 1.0% (31/2966) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143763573). -

Autosomal dominant nonsyndromic hearing loss 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T;.;T;.;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
MetaRNN	Benign	0.0092	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.3	.;.;.;D;D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.024	.;.;.;D;D;.
Sift4G	Benign	0.065	T;.;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.70
MVP		0.54
MPC		1.8
ClinPred		0.075	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.53

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: rs143763573; hg19: chr5-140907186;