chr4-145639164-C-A

Variant names:

• chr4-145639164-C-A
• NM_172250.3:c.25C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172250.3(MMAA):​c.25C>A​(p.His9Asn) variant causes a missense 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MMAA NM_172250.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.469
• Publications: 0 publications found

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]

MMAA Gene-Disease associations (from GenCC):

• methylmalonic aciduria, cblA type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

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=0.072826445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAA	NM_172250.3	c.25C>A	p.His9Asn	missense_variant	Exon 2 of 7	ENST00000649156.2	NP_758454.1
MMAA	NM_001375644.1	c.25C>A	p.His9Asn	missense_variant	Exon 2 of 7		NP_001362573.1
MMAA	XM_011531684.4	c.25C>A	p.His9Asn	missense_variant	Exon 2 of 7		XP_011529986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2	c.25C>A	p.His9Asn	missense_variant	Exon 2 of 7		NM_172250.3	ENSP00000497008.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Methylmalonic aciduria, cblA type Uncertain:1

May 21, 2025

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.17	T;.;T;T;T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.69	.;T;.;.;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.073	T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.0	M;.;M;M;M;.
PhyloP100		0.47
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.82	.;.;N;.;.;.
REVEL	Benign	0.14
Sift	Benign	0.18	.;.;T;.;.;.
Sift4G	Benign	0.46	.;.;T;.;.;T
Polyphen		0.0	B;.;B;B;B;.
Vest4		0.28, 0.35
MutPred		0.36		Loss of glycosylation at P8 (P = 0.1368);Loss of glycosylation at P8 (P = 0.1368);Loss of glycosylation at P8 (P = 0.1368);Loss of glycosylation at P8 (P = 0.1368);Loss of glycosylation at P8 (P = 0.1368);Loss of glycosylation at P8 (P = 0.1368);
MVP		0.61
MPC		0.13
ClinPred		0.052	T
GERP RS		1.7
Varity_R		0.036
gMVP		0.41
Mutation Taster		=290/10	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

hg19: chr4-146560316;