5-141515918-A-T

Position:

• chr5-141515918-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005219.5(DIAPH1):​c.*933T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 151,318 control chromosomes in the GnomAD database, including 1,349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1349 hom., cov: 32)
  • Exomes 𝑓: 0.061 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.91

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-141515918-A-T is Benign according to our data. Variant chr5-141515918-A-T is described in ClinVar as [Benign]. Clinvar id is 351272.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.*933T>A		3_prime_UTR_variant	28/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.*933T>A		3_prime_UTR_variant	28/28	5	NM_005219.5	ENSP00000373706	A2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19624 AN: 151104 Hom.: 1350 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0122

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0948

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0612 AC: 6 AN: 98 Hom.: 0 Cov.: 0 AF XY: 0.0625 AC XY: 3 AN XY: 48

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0750

Gnomad4 NFE exome AF: 0.0333

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.130 AC: 19631 AN: 151220 Hom.: 1349 Cov.: 32 AF XY: 0.129 AC XY: 9560 AN XY: 73912

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.0124

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.0948

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.128

Alfa AF: 0.121 Hom.: 129

Bravo AF: 0.134

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.9
DANN	Benign	0.65

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: rs55798800; hg19: chr5-140895485;