4-145639140-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_172250.3(MMAA):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMAA NM_172250.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.467

Genes affected

MMAA (HGNC:18871): (metabolism of cobalamin associated A) The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-145639140-A-G is Pathogenic according to our data. Variant chr4-145639140-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551711.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAA	NM_172250.3	c.1A>G	p.Met1?	start_lost	2/7	ENST00000649156.2
MMAA	NM_001375644.1	c.1A>G	p.Met1?	start_lost	2/7
MMAA	XM_011531684.4	c.1A>G	p.Met1?	start_lost	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAA	ENST00000649156.2	c.1A>G	p.Met1?	start_lost	2/7		NM_172250.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria, cblA type Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

May 04, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	2.3
Dann	Benign	0.64
DEOGEN2	Benign	0.15	T;.;T;T;T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.051	N
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	N;N
Polyphen		0.0	B;.;B;B;B;.
Vest4		0.13, 0.17
MutPred		0.67		Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);
MVP		0.38
ClinPred		0.14	T
GERP RS		1.1
Varity_R		0.042
gMVP		0.50

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: rs1553957856; hg19: chr4-146560292;