chr5-141515918-A-AT

Position:

• chr5-141515918-A-AT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005219.5(DIAPH1):​c.*932_*933insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 151,278 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00092 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.15

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.*932_*933insA		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.*932_*933insA		3_prime_UTR_variant	28/28	5	NM_005219.5	ENSP00000373706	A2

Frequencies

GnomAD3 genomes AF: 0.000926 AC: 140 AN: 151162 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000725

Gnomad ASJ AF: 0.00665

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000944

Gnomad OTH AF: 0.00434

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 98 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 48

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000919 AC: 139 AN: 151278 Hom.: 2 Cov.: 33 AF XY: 0.000920 AC XY: 68 AN XY: 73936

Gnomad4 AFR AF: 0.000583

Gnomad4 AMR AF: 0.000724

Gnomad4 ASJ AF: 0.00665

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000836

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000944

Gnomad4 OTH AF: 0.00429

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nonsyndromic Hearing Loss, Mixed Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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: rs550954506; hg19: chr5-140895485;