5-141527619-A-G

Position:

• chr5-141527619-A-G

Variant summary

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

The NM_005219.5(DIAPH1):​c.3227T>C​(p.Phe1076Ser) variant causes a missense change involving the alteration of a 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: 30)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.25

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.3227T>C	p.Phe1076Ser	missense_variant	24/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3227T>C	p.Phe1076Ser	missense_variant	24/28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.3200T>C	p.Phe1067Ser	missense_variant	23/27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.3227T>C	p.Phe1076Ser	missense_variant	24/29			ENSP00000494675.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;T;.;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.3	.;.;.;D;D;.
REVEL	Uncertain	0.39
Sift	Benign	0.14	.;.;.;T;T;.
Sift4G	Benign	0.24	T;.;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.56
MutPred		0.50		Gain of phosphorylation at F1076 (P = 0.0309);Gain of phosphorylation at F1076 (P = 0.0309);.;.;Gain of phosphorylation at F1076 (P = 0.0309);.;
MVP		0.51
MPC		2.0
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143763573; hg19: chr5-140907186;