rs375375478

chr5-141573477-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005219.5(DIAPH1):c.2358+15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000915 in 1,321,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.333

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-141573477-G-C is Benign according to our data. Variant chr5-141573477-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000377 (56/148542) while in subpopulation AFR AF= 0.00126 (51/40338). AF 95% confidence interval is 0.000988. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5	c.2358+15C>G		intron_variant		ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.2358+15C>G		intron_variant		5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.2331+15C>G		intron_variant		5		P4
DIAPH1	ENST00000647433.1	c.2358+15C>G		intron_variant				A2

Frequencies

GnomAD3 genomes AF: 0.000377 AC: 56 AN: 148454 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000201

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: 0.000981

GnomAD3 exomes AF: 0.0000742 AC: 18 AN: 242530 Hom.: 0 AF XY: 0.0000453 AC XY: 6 AN XY: 132510

Gnomad AFR exome AF: 0.00108

Gnomad AMR exome AF: 0.0000581

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000554 AC: 65 AN: 1173456 Hom.: 0 Cov.: 38 AF XY: 0.0000489 AC XY: 29 AN XY: 593456

Gnomad4 AFR exome AF: 0.00186

Gnomad4 AMR exome AF: 0.0000935

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000290

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000348

Gnomad4 OTH exome AF: 0.000142

GnomAD4 genome AF: 0.000377 AC: 56 AN: 148542 Hom.: 0 Cov.: 28 AF XY: 0.000276 AC XY: 20 AN XY: 72460

Gnomad4 AFR AF: 0.00126

Gnomad4 AMR AF: 0.000201

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: 0.000973

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000442

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

2358+15C>G in Intron 16 of DIAPH1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 0.1% (4/2940) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS). -

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

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	10
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375375478; hg19: chr5-140953044;