rs9593

chr12-109557065-A-Cchr12-109557065-A-Gchr12-109557065-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_052845.4(MMAB):c.716T>G(p.Met239Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 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. M239K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MMAB NM_052845.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210

Genes affected

MMAB (HGNC:19331): (metabolism of cobalamin associated B) This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a chain Corrinoid adenosyltransferase MMAB (size 217) in uniprot entity MMAB_HUMAN there are 32 pathogenic changes around while only 10 benign (76%) in NM_052845.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.05167088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAB	NM_052845.4	c.716T>G	p.Met239Arg	missense_variant	9/9	ENST00000545712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAB	ENST00000545712.7	c.716T>G	p.Met239Arg	missense_variant	9/9	1	NM_052845.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461114 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	14
Dann	Benign	0.40
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.080	T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-1.7	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.9	N;.
REVEL	Benign	0.19
Sift	Benign	0.50	T;.
Sift4G	Benign	0.40	T;T
Polyphen		0.0	B;.
Vest4		0.056
MutPred		0.23		Gain of methylation at K240 (P = 0.0267);.;
MVP		0.56
MPC		0.34
ClinPred		0.058	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.26
gMVP		0.41

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

Other links and lift over

dbSNP: rs9593; hg19: chr12-109994870;