dbSNP rs373520931: DIAPH1:p.Pro721Leu (chr5-141573688-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005219.5(DIAPH1):c.2162C>T(p.Pro721Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P721H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.45

Publications

0 publications found

Variant links:

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]

DIAPH1 Gene-Disease associations (from GenCC):

DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal dominant nonsyndromic hearing loss 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

DIAPH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3020717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5 link	c.2162C>T	p.Pro721Leu	missense_variant	Exon 16 of 28	ENST00000389054.8	NP_005210.3	O60610-1Q6URC4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DIAPH1	ENST00000389054.8 link	c.2162C>T	p.Pro721Leu	missense_variant	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5 link	c.2135C>T	p.Pro712Leu	missense_variant	Exon 15 of 27	5		ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1 link	c.2162C>T	p.Pro721Leu	missense_variant	Exon 16 of 29			ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454180

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33348

American (AMR)

AF:

0.00

AC:

AN:

43868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106618

Other (OTH)

AF:

0.00

AC:

AN:

60060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.0061

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.12

T;.;T;.;T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;T;T;T;T;T

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.30

T;T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.2

N;.;D;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.70

T;.;T;T;T;T

Sift4G

Benign

0.073

T;.;T;T;T;T

Polyphen

0.032

B;.;.;.;.;.

Vest4

0.45

MutPred

0.43

Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);.;.;Loss of relative solvent accessibility (P = 0.008);.;

MVP

0.75

MPC

0.12

ClinPred

0.94

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.17

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over