rs876657451

Positions:

• chr5-141573783-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005219.5(DIAPH1):​c.2067A>C​(p.Pro689=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.54

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 5-141573783-T-G is Benign according to our data. Variant chr5-141573783-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 227301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.54 with no splicing effect.
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.2067A>C	p.Pro689=	synonymous_variant	16/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.2067A>C	p.Pro689=	synonymous_variant	16/28	5	NM_005219.5	ENSP00000373706	A2
DIAPH1	ENST00000518047.5	c.2040A>C	p.Pro680=	synonymous_variant	15/27	5		ENSP00000428268	P4
DIAPH1	ENST00000647433.1	c.2067A>C	p.Pro689=	synonymous_variant	16/29			ENSP00000494675	A2

Frequencies

GnomAD3 genomes AF: 0.000989 AC: 30 AN: 30344 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00185

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000543 AC: 6 AN: 110418 Hom.: 0 AF XY: 0.0000703 AC XY: 4 AN XY: 56866

Gnomad AFR exome AF: 0.000286

Gnomad AMR exome AF: 0.0000654

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000403

Gnomad OTH exome AF: 0.000381

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000438 AC: 36 AN: 821984 Hom.: 0 Cov.: 29 AF XY: 0.0000583 AC XY: 23 AN XY: 394362

Gnomad4 AFR exome AF: 0.000108

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.000141

Gnomad4 FIN exome AF: 0.0000420

Gnomad4 NFE exome AF: 0.0000344

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome AF: 0.000987 AC: 30 AN: 30396 Hom.: 0 Cov.: 0 AF XY: 0.000945 AC XY: 14 AN XY: 14810

Gnomad4 AFR AF: 0.000539

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0206 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 06, 2016	p.Pro689Pro in exon 16 of DIAPH1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.25
DANN	Benign	0.64

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: rs876657451; hg19: chr5-140953350; COSMIC: COSV99526149; COSMIC: COSV99526149;