Genetic Variant MAMDC2:p.Ala27Ser (chr9-70044628-G-T) – 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_153267.5(MAMDC2):c.79G>T(p.Ala27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A27T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MAMDC2
NM_153267.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.16

Publications

0 publications found

Variant links:

Genes affected

MAMDC2 (HGNC:23673): (MAM domain containing 2) Predicted to enable glycosaminoglycan binding activity. Predicted to act upstream of or within peptide cross-linking via chondroitin 4-sulfate glycosaminoglycan. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

MAMDC2 links:

MAMDC2-AS1 (HGNC:48719): (MAMDC2 antisense RNA 1)

MAMDC2-AS1 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=0.09441218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MAMDC2	NM_153267.5 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 2 of 14	ENST00000377182.5	NP_694999.3
MAMDC2	NM_001347990.2 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 2 of 12		NP_001334919.1
MAMDC2	NR_125850.1 link	n.696G>T		non_coding_transcript_exon_variant	Exon 2 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAMDC2	ENST00000377182.5 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 2 of 14	1	NM_153267.5	ENSP00000366387.4		Q7Z304-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000639

AC:

AN:

156514

AF XY:

0.0000121

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399092

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31590

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35740

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078948

Other (OTH)

AF:

0.00

AC:

AN:

57978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000145

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0035

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.74

M_CAP

Benign

0.0056

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.050

PhyloP100

2.2

PrimateAI

Benign

0.44

PROVEAN

Benign

0.83

REVEL

Benign

0.027

Sift

Benign

0.69

Sift4G

Benign

0.79

Polyphen

0.0090

Vest4

0.29

MutPred

0.43

Gain of disorder (P = 0.0149);

MVP

0.24

MPC

0.17

ClinPred

0.22

GERP RS

2.7

Varity_R

0.073

gMVP

0.44

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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9-70044628-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over