rs199749212

Positions:

• chr5-141573626-G-A
• chr5-141573626-G-C

Variant summary

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

The NM_005219.5(DIAPH1):​c.2224C>T​(p.Pro742Ser) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P742A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 28)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.09

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	UniProt
DIAPH1	NM_005219.5	c.2224C>T	p.Pro742Ser	missense_variant	16/28	ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.2224C>T	p.Pro742Ser	missense_variant	16/28	5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.2197C>T	p.Pro733Ser	missense_variant	15/27	5		P4
DIAPH1	ENST00000647433.1	c.2224C>T	p.Pro742Ser	missense_variant	16/29			A2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;T;.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N;.;.;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.61	T;.;.;T;T;T
Sift4G	Uncertain	0.030	D;.;D;D;D;D
Polyphen		0.97	D;.;.;.;.;.
Vest4		0.30
MutPred		0.50		Gain of phosphorylation at P742 (P = 0.0023);Gain of phosphorylation at P742 (P = 0.0023);.;.;Gain of phosphorylation at P742 (P = 0.0023);.;
MVP		0.96
MPC		0.12
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.074
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-140953193;