Genetic Variant NM_005219.5:c.2009C>G (chr5-141573841-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005219.5(DIAPH1):c.2009C>G(p.Pro670Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,375,690 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P670L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.50

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

DIAPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIAPH1	NM_005219.5	MANE Select	c.2009C>G	p.Pro670Arg	missense	Exon 16 of 28	NP_005210.3
DIAPH1	NM_001079812.3		c.1982C>G	p.Pro661Arg	missense	Exon 15 of 27	NP_001073280.1	O60610-3
DIAPH1	NM_001314007.2		c.2009C>G	p.Pro670Arg	missense	Exon 16 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.2009C>G	p.Pro670Arg	missense	Exon 16 of 28	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5	TSL:5	c.1982C>G	p.Pro661Arg	missense	Exon 15 of 27	ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1		c.2009C>G	p.Pro670Arg	missense	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1375690

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

674018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32028

American (AMR)

AF:

0.00

AC:

AN:

34700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22408

East Asian (EAS)

AF:

0.00

AC:

AN:

36756

South Asian (SAS)

AF:

0.00

AC:

AN:

72702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1066100

Other (OTH)

AF:

0.00

AC:

AN:

57130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.36

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.1

PhyloP100

5.5

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.43

Sift

Uncertain

0.012

Sift4G

Benign

0.071

Polyphen

1.0

Vest4

0.46

MutPred

0.57

Gain of methylation at P670 (P = 0.0178)

MVP

0.87

MPC

0.12

ClinPred

0.89

GERP RS

4.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.12

gMVP

0.26

Mutation Taster

=20/80

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over