DIAPH1 p.Ala963Ala

Variant names:

• chr5-141528830-A-A
• NM_005219.5:c.

Your query was ambiguous. Multiple possible variants found:

• chr5-141528831--
• chr5-141528831-T-A
• chr5-141528831-T-G
• chr5-141528831-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005219.5(DIAPH1):​c. variant causes a exon region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIAPH1 NM_005219.5 exon_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.891
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.		exon_region	Exon 22 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.		exon_region	Exon 21 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.		exon_region	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.		exon_region	Exon 22 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.		exon_region	Exon 21 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.		exon_region	Exon 22 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.89

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-140908397;