9-70044667-G-T

Variant names:

• chr9-70044667-G-T
• rs776057039
• NM_153267.5:c.118G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153267.5(MAMDC2):​c.118G>T​(p.Ala40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000238 in 1,551,718 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (1 hom.)
• Consequence: MAMDC2 NM_153267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.844
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042738855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAMDC2	NM_153267.5	c.118G>T	p.Ala40Ser	missense_variant	Exon 2 of 14	ENST00000377182.5	NP_694999.3
MAMDC2	NM_001347990.2	c.118G>T	p.Ala40Ser	missense_variant	Exon 2 of 12		NP_001334919.1
MAMDC2	NR_125850.1	n.735G>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	c.118G>T	p.Ala40Ser	missense_variant	Exon 2 of 14	1	NM_153267.5	ENSP00000366387.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 156582 AF XY: 0.00

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: 0.0000330

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 34 AN: 1399364 Hom.: 1 Cov.: 31 AF XY: 0.0000319 AC XY: 22 AN XY: 690196

African (AFR) AF: 0.000411 AC: 13 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35742

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49258

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5676

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078970

Other (OTH) AF: 0.000121 AC: 7 AN: 58006

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74494

African (AFR) AF: 0.0000481 AC: 2 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000151 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.118G>T (p.A40S) alteration is located in exon 2 (coding exon 2) of the MAMDC2 gene. This alteration results from a G to T substitution at nucleotide position 118, causing the alanine (A) at amino acid position 40 to be replaced by a serine (S). 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	0.076
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.23	N
PhyloP100		0.84
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.030
Sift	Benign	0.61	T
Sift4G	Benign	0.64	T
Polyphen		0.021	B
Vest4		0.20
MutPred		0.42		Gain of loop (P = 0.069);
MVP		0.21
MPC		0.13
ClinPred		0.026	T
GERP RS		-0.32
Varity_R		0.097
gMVP		0.32
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs776057039; hg19: chr9-72659583;