5-141588240-C-G

Position:

• chr5-141588240-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005219.5(DIAPH1):​c.128G>C​(p.Arg43Pro) variant causes a missense change. 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 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.01

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.128G>C	p.Arg43Pro	missense_variant	2/28	ENST00000389054.8	NP_005210.3
DIAPH1	NM_001314007.2	c.128G>C	p.Arg43Pro	missense_variant	2/29		NP_001300936.1
DIAPH1	XM_047416885.1	c.62G>C	p.Arg21Pro	missense_variant	2/28		XP_047272841.1
DIAPH1	NM_001079812.3	c.118-1043G>C		intron_variant			NP_001073280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.128G>C	p.Arg43Pro	missense_variant	2/28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000647433.1	c.128G>C	p.Arg43Pro	missense_variant	2/29			ENSP00000494675.1
DIAPH1	ENST00000518047.5	c.118-1043G>C		intron_variant		5		ENSP00000428268.2
DIAPH1	ENST00000523100.5	n.128G>C		non_coding_transcript_exon_variant	2/11	5		ENSP00000428208.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.4	N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.047	D;.;D
Sift4G	Benign	0.18	T;.;T
Polyphen		1.0	D;.;.
Vest4		0.53
MutPred		0.26		Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);
MVP		0.93
MPC		1.1
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.54
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs727502964; hg19: chr5-140967807;