5-141515223-GGGA-G

Position:

• chr5-141515223-GGGA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005219.5(DIAPH1):​c.*1625_*1627del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 152,598 control chromosomes in the GnomAD database, including 45 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (45 hom., cov: 32)
  • Exomes 𝑓: 0.025 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.14

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 -10 ACMG points.

• BP6: Variant 5-141515223-GGGA-G is Benign according to our data. Variant chr5-141515223-GGGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 351257.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2530/152232) while in subpopulation NFE AF= 0.0256 (1743/68010). AF 95% confidence interval is 0.0246. There are 45 homozygotes in gnomad4. There are 1200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2530 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.*1625_*1627del		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.*1625_*1627del		3_prime_UTR_variant	28/28	5	NM_005219.5	ENSP00000373706	A2

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2530 AN: 152114 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00343

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.0246 AC: 9 AN: 366 Hom.: 0 AF XY: 0.0225 AC XY: 5 AN XY: 222

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0166 AC: 2530 AN: 152232 Hom.: 45 Cov.: 32 AF XY: 0.0161 AC XY: 1200 AN XY: 74414

Gnomad4 AFR AF: 0.00342

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0378

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0286 Hom.: 15

Bravo AF: 0.0133

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nonsyndromic Hearing Loss, Mixed Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs202157915; hg19: chr5-140894790;