rs1003389476

Variant names:

• chr5-141527689-C-A
• rs1003389476
• NM_005219.5:c.3157G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_005219.5(DIAPH1):​c.3157G>T​(p.Glu1053*) 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
• Publications: 0 publications found

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]

DIAPH1 Gene-Disease associations (from GenCC):

• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	NM_005219.5	MANE Select	c.3157G>T	p.Glu1053*	stop_gained	Exon 24 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.3130G>T	p.Glu1044*	stop_gained	Exon 23 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.3157G>T	p.Glu1053*	stop_gained	Exon 24 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.3157G>T	p.Glu1053*	stop_gained	Exon 24 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.3130G>T	p.Glu1044*	stop_gained	Exon 23 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.3157G>T	p.Glu1053*	stop_gained	Exon 24 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111228 Hom.: 0 Cov.: 25

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

GnomAD2 exomes AF: 0.0000403 AC: 7 AN: 173584 AF XY: 0.0000313

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000270

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000722 AC: 1 AN: 13856

American (AMR) AF: 0.0000838 AC: 2 AN: 23878

Ashkenazi Jewish (ASJ) AF: 0.0000760 AC: 1 AN: 13162

East Asian (EAS) AF: 0.0000976 AC: 2 AN: 20488

South Asian (SAS) AF: 0.000126 AC: 6 AN: 47454

European-Finnish (FIN) AF: 0.0000271 AC: 1 AN: 36946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2022

European-Non Finnish (NFE) AF: 0.000188 AC: 81 AN: 431544

Other (OTH) AF: 0.0000780 AC: 2 AN: 25642

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000352 AC: 1 AN: 28422

American (AMR) AF: 0.00 AC: 0 AN: 9230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3042

East Asian (EAS) AF: 0.00 AC: 0 AN: 3698

South Asian (SAS) AF: 0.00 AC: 0 AN: 3368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 184

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57170

Other (OTH) AF: 0.00 AC: 0 AN: 1420

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant nonsyndromic hearing loss 1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.3
Vest4		0.89
GERP RS		5.6
Mutation Taster		=8/192	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1003389476; hg19: chr5-140907256;