rs750444501

Variant names:

• chr5-141528834-A-G
• rs750444501
• NM_005219.5:c.2886T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_005219.5(DIAPH1):​c.2886T>C​(p.Ala962Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,614,258 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 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.33
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-141528834-A-G is Benign according to our data. Variant chr5-141528834-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 475704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.33 with no splicing effect.

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.2886T>C	p.Ala962Ala	synonymous	Exon 22 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.2859T>C	p.Ala953Ala	synonymous	Exon 21 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.2886T>C	p.Ala962Ala	synonymous	Exon 22 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.2886T>C	p.Ala962Ala	synonymous	Exon 22 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.2859T>C	p.Ala953Ala	synonymous	Exon 21 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.2886T>C	p.Ala962Ala	synonymous	Exon 22 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000136 AC: 34 AN: 249274 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.000102 AC XY: 74 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000102 AC: 113 AN: 1112012

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74512

African (AFR) AF: 0.0000721 AC: 3 AN: 41582

American (AMR) AF: 0.000718 AC: 11 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000208

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.4
DANN	Benign	0.45
PhyloP100		-2.3
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs750444501; hg19: chr5-140908401;