rs1554200929

Positions:

• chr5-141526329-T-A
• chr5-141526329-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005219.5(DIAPH1):​c.3406A>T​(p.Met1136Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1136I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28407326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.3406A>T	p.Met1136Leu	missense_variant	25/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3406A>T	p.Met1136Leu	missense_variant	25/28	5	NM_005219.5	ENSP00000373706	A2
DIAPH1	ENST00000518047.5	c.3379A>T	p.Met1127Leu	missense_variant	24/27	5		ENSP00000428268	P4
DIAPH1	ENST00000647433.1	c.3406A>T	p.Met1136Leu	missense_variant	25/29			ENSP00000494675	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 542356). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1136 of the DIAPH1 protein (p.Met1136Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;.;T;.;T;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.
MutationTaster	Benign	0.98	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.85	.;.;.;N;N;.
REVEL	Benign	0.071
Sift	Benign	0.043	.;.;.;D;D;.
Sift4G	Benign	0.20	T;.;T;T;T;T
Polyphen		0.032	B;.;.;.;.;.
Vest4		0.28
MutPred		0.57		Loss of disorder (P = 0.123);Loss of disorder (P = 0.123);.;.;Loss of disorder (P = 0.123);.;
MVP		0.58
MPC		0.51
ClinPred		0.62	D
GERP RS		5.4
Varity_R		0.11
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554200929; hg19: chr5-140905896;