rs1003389476

Positions:

• chr5-141527689-C-A
• chr5-141527689-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_005219.5(DIAPH1):​c.3157G>T​(p.Glu1053Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5	c.3157G>T	p.Glu1053Ter	stop_gained	24/28	ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3157G>T	p.Glu1053Ter	stop_gained	24/28	5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.3130G>T	p.Glu1044Ter	stop_gained	23/27	5		P4
DIAPH1	ENST00000647433.1	c.3157G>T	p.Glu1053Ter	stop_gained	24/29			A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 111228 Hom.: 0 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.0000352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000156 AC: 96 AN: 614992 Hom.: 0 Cov.: 28 AF XY: 0.000132 AC XY: 42 AN XY: 318734

Gnomad4 AFR exome AF: 0.0000722

Gnomad4 AMR exome AF: 0.0000838

Gnomad4 ASJ exome AF: 0.0000760

Gnomad4 EAS exome AF: 0.0000976

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.0000271

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.0000780

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000899 AC: 1 AN: 111260 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 51520

Gnomad4 AFR AF: 0.0000352

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
Vest4		0.89
GERP RS		5.6

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: rs1003389476; hg19: chr5-140907256;