chr5-141573751-A-C

Variant names:

• chr5-141573751-A-C
• NM_005219.5:c.2099T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_005219.5(DIAPH1):​c.2099T>G​(p.Ile700Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000864 in 1,157,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. I700N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.731

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-141573751-A-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.13021907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.2099T>G	p.Ile700Ser	missense_variant	Exon 16 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.2099T>G	p.Ile700Ser	missense_variant	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.2072T>G	p.Ile691Ser	missense_variant	Exon 15 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.2099T>G	p.Ile700Ser	missense_variant	Exon 16 of 29			ENSP00000494675.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 8.64e-7 AC: 1 AN: 1157462 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 566990

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.087	T;.;T;.;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.60	T;T;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;.;.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.038	D;.;.;D;D;D
Sift4G	Uncertain	0.047	D;.;T;D;D;T
Polyphen		0.077	B;.;.;.;.;.
Vest4		0.21
MutPred		0.42		Gain of phosphorylation at I700 (P = 4e-04);Gain of phosphorylation at I700 (P = 4e-04);.;.;Gain of phosphorylation at I700 (P = 4e-04);.;
MVP		0.70
MPC		0.17
ClinPred		0.17	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.087

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: chr5-140953318;