8-22069889-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001387751.1(DMTN):​c.403C>T​(p.Arg135Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

DMTN
NM_001387751.1 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.18
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.116784126).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DMTNNM_001387751.1 linkc.403C>T p.Arg135Cys missense_variant Exon 7 of 16 ENST00000358242.6 NP_001374680.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DMTNENST00000358242.6 linkc.403C>T p.Arg135Cys missense_variant Exon 7 of 16 5 NM_001387751.1 ENSP00000350977.3 Q08495-1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000994
AC:
25
AN:
251430
Hom.:
0
AF XY:
0.0000809
AC XY:
11
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000492
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000623
AC:
91
AN:
1461840
Hom.:
0
Cov.:
31
AF XY:
0.0000454
AC XY:
33
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000514
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000567
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000567
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.403C>T (p.R135C) alteration is located in exon 7 (coding exon 6) of the DMTN gene. This alteration results from a C to T substitution at nucleotide position 403, causing the arginine (R) at amino acid position 135 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.23
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.17
.;.;T;.;.;.;T;T;.;T;T;.;T;T;.;.
Eigen
Benign
0.14
Eigen_PC
Benign
0.15
FATHMM_MKL
Benign
0.59
D
LIST_S2
Uncertain
0.95
D;D;.;.;D;D;D;D;.;.;.;D;D;.;.;.
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.90
.;L;L;.;.;.;.;.;.;L;L;.;L;L;L;L
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.6
D;N;N;D;N;N;D;D;D;N;N;D;N;N;N;N
REVEL
Benign
0.19
Sift
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.071
T;T;T;T;T;T;T;T;D;T;T;D;T;T;T;T
Polyphen
1.0, 1.0
.;D;D;.;.;.;.;.;.;D;D;.;D;D;D;D
Vest4
0.66, 0.67, 0.65, 0.68, 0.56, 0.65, 0.59, 0.60, 0.64, 0.66
MutPred
0.30
.;Loss of phosphorylation at S138 (P = 0.0483);Loss of phosphorylation at S138 (P = 0.0483);.;.;.;.;.;Loss of phosphorylation at S138 (P = 0.0483);Loss of phosphorylation at S138 (P = 0.0483);Loss of phosphorylation at S138 (P = 0.0483);Loss of phosphorylation at S138 (P = 0.0483);Loss of phosphorylation at S138 (P = 0.0483);Loss of phosphorylation at S138 (P = 0.0483);Loss of phosphorylation at S138 (P = 0.0483);Loss of phosphorylation at S138 (P = 0.0483);
MVP
0.49
MPC
0.87
ClinPred
0.20
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748499265; hg19: chr8-21927400; API