Genetic Variant MAMDC4:p.Arg157Trp (chr9-136853791-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_206920.3(MAMDC4):c.469C>T(p.Arg157Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MAMDC4
NM_206920.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.585

Variant links:

Genes affected

MAMDC4 (HGNC:24083): (MAM domain containing 4) Predicted to be involved in protein transport. Predicted to be located in membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MAMDC4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAMDC4	NM_206920.3 link	c.469C>T	p.Arg157Trp	missense_variant	Exon 5 of 27	ENST00000317446.7	NP_996803.2	Q6UXC1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAMDC4	ENST00000317446.7 link	c.469C>T	p.Arg157Trp	missense_variant	Exon 5 of 27	1	NM_206920.3	ENSP00000319388.2	Q6UXC1-2
MAMDC4	ENST00000485732.5 link	n.905C>T		non_coding_transcript_exon_variant	Exon 5 of 25	1
MAMDC4	ENST00000445819.5 link	c.469C>T	p.Arg157Trp	missense_variant	Exon 5 of 29	5		ENSP00000411339.1	Q6UXC1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000814

AC:

AN:

245602

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

133996

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457886

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

725040

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.469C>T (p.R157W) alteration is located in exon 5 (coding exon 5) of the MAMDC4 gene. This alteration results from a C to T substitution at nucleotide position 469, causing the arginine (R) at amino acid position 157 to be replaced by a tryptophan (W). 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

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

.;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.083

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0050

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.57

MutPred

0.71

Gain of catalytic residue at R157 (P = 0.0066);Gain of catalytic residue at R157 (P = 0.0066);

MVP

0.24

MPC

0.18

ClinPred

0.91

GERP RS

1.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.15

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over