NM_005219.5:c.2373C>A

Variant names:

• chr5-141572026-G-T
• NM_005219.5:c.2373C>A
• DIAPH1 p.Asp791Glu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005219.5(DIAPH1):​c.2373C>A​(p.Asp791Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D791D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.300
• 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: ClinGen, Orphanet
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08143005).

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.2373C>A	p.Asp791Glu	missense	Exon 17 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.2346C>A	p.Asp782Glu	missense	Exon 16 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.2373C>A	p.Asp791Glu	missense	Exon 17 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.2373C>A	p.Asp791Glu	missense	Exon 17 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.2346C>A	p.Asp782Glu	missense	Exon 16 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.2373C>A	p.Asp791Glu	missense	Exon 17 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.63
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.30
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.036
gMVP		0.25
Mutation Taster		=90/10	polymorphism

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

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

Other links and lift over

hg19: chr5-140951593;