chr9-70140228-T-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_153267.5(MAMDC2):āc.1078T>Gā(p.Trp360Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000312 in 1,600,304 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 (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
MAMDC2
NM_153267.5 missense
NM_153267.5 missense
Scores
11
3
5
Clinical Significance
Conservation
PhyloP100: 6.58
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAMDC2 | NM_153267.5 | c.1078T>G | p.Trp360Gly | missense_variant | 8/14 | ENST00000377182.5 | |
MAMDC2 | NM_001347990.2 | c.1078T>G | p.Trp360Gly | missense_variant | 8/12 | ||
MAMDC2 | NR_125850.1 | n.1695T>G | non_coding_transcript_exon_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAMDC2 | ENST00000377182.5 | c.1078T>G | p.Trp360Gly | missense_variant | 8/14 | 1 | NM_153267.5 | P1 | |
MAMDC2-AS1 | ENST00000591368.5 | n.408+7753A>C | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000847 AC: 2AN: 236256Hom.: 0 AF XY: 0.0000156 AC XY: 2AN XY: 128100
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GnomAD4 exome AF: 0.00000207 AC: 3AN: 1448124Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2AN XY: 720246
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2023 | The c.1078T>G (p.W360G) alteration is located in exon 8 (coding exon 8) of the MAMDC2 gene. This alteration results from a T to G substitution at nucleotide position 1078, causing the tryptophan (W) at amino acid position 360 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at