Genetic Variant NM_001387751.1:c.561C>G (chr8-22070291-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001387751.1(DMTN):c.561C>G(p.Ile187Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,358 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. Synonymous variant affecting the same amino acid position (i.e. I187I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DMTN
NM_001387751.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -6.17

Publications

0 publications found

Variant links:

Genes affected

DMTN (HGNC:3382): (dematin actin binding protein) The protein encoded by this gene is an actin binding and bundling protein that plays a structural role in erythrocytes, by stabilizing and attaching the spectrin/actin cytoskeleton to the erythrocyte membrane in a phosphorylation-dependent manner. This protein contains a core domain in the N-terminus, and a headpiece domain in the C-terminus that binds F-actin. When purified from erythrocytes, this protein exists as a trimer composed of two 48 kDa polypeptides and a 52 kDa polypeptide. The different subunits arise from alternative splicing in the 3' coding region, where the headpiece domain is located. Disruption of this gene has been correlated with the autosomal dominant Marie Unna hereditary hypotrichosis disease, while loss of heterozygosity of this gene is thought to play a role in prostate cancer progression. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2014]

DMTN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22843248).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387751.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMTN	NM_001387751.1	MANE Select	c.561C>G	p.Ile187Met	missense	Exon 8 of 16	NP_001374680.1	Q08495-1
DMTN	NM_001114135.5		c.561C>G	p.Ile187Met	missense	Exon 8 of 16	NP_001107607.1	Q08495-1
DMTN	NM_001114136.3		c.561C>G	p.Ile187Met	missense	Exon 8 of 16	NP_001107608.1	Q08495-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMTN	ENST00000358242.6	TSL:5 MANE Select	c.561C>G	p.Ile187Met	missense	Exon 8 of 16	ENSP00000350977.3	Q08495-1
DMTN	ENST00000265800.9	TSL:5	c.561C>G	p.Ile187Met	missense	Exon 8 of 16	ENSP00000265800.5	Q08495-1
DMTN	ENST00000432128.6	TSL:5	c.561C>G	p.Ile187Met	missense	Exon 8 of 16	ENSP00000416111.1	Q08495-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461358

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111754

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Pathogenic

0.79

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Benign

7.9

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.82

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.044

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.7

PhyloP100

-6.2

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.6

REVEL

Benign

0.23

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.85

MutPred

0.17

Loss of phosphorylation at T189 (P = 0.1077)

MVP

0.33

MPC

1.0

ClinPred

0.96

GERP RS

-5.3

Varity_R

0.43

gMVP

0.60

Mutation Taster

=61/39

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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