5-141588240-C-A

Position:

• chr5-141588240-C-A

Variant summary

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

The NM_005219.5(DIAPH1):​c.128G>T​(p.Arg43Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,230 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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>T	p.Arg43Leu	missense_variant	2/28	ENST00000389054.8	NP_005210.3
DIAPH1	NM_001314007.2	c.128G>T	p.Arg43Leu	missense_variant	2/29		NP_001300936.1
DIAPH1	XM_047416885.1	c.62G>T	p.Arg21Leu	missense_variant	2/28		XP_047272841.1
DIAPH1	NM_001079812.3	c.118-1043G>T		intron_variant			NP_001073280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.128G>T	p.Arg43Leu	missense_variant	2/28	5	NM_005219.5	ENSP00000373706	A2
DIAPH1	ENST00000647433.1	c.128G>T	p.Arg43Leu	missense_variant	2/29			ENSP00000494675	A2
DIAPH1	ENST00000518047.5	c.118-1043G>T		intron_variant		5		ENSP00000428268	P4
DIAPH1	ENST00000523100.5	c.128G>T	p.Arg43Leu	missense_variant, NMD_transcript_variant	2/11	5		ENSP00000428208

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249056 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460230 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726524

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.6	N;.;N
REVEL	Uncertain	0.50
Sift	Benign	0.049	D;.;D
Sift4G	Benign	0.14	T;.;T
Polyphen		1.0	D;.;.
Vest4		0.51
MutPred		0.32		Loss of MoRF binding (P = 0.0166);Loss of MoRF binding (P = 0.0166);Loss of MoRF binding (P = 0.0166);
MVP		0.93
MPC		0.93
ClinPred		0.83	D
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.31
gMVP		0.42

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;