rs754545360

Variant names:

• chr4-145639536-C-A
• rs754545360
• NM_172250.3:c.397C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-145639536-C-A
• chr4-145639536-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_172250.3(MMAA):​c.397C>A​(p.Gln133Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MMAA NM_172250.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3108667).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172250.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAA	NM_172250.3	MANE Select	c.397C>A	p.Gln133Lys	missense	Exon 2 of 7	NP_758454.1
	MMAA	NM_001375644.1		c.397C>A	p.Gln133Lys	missense	Exon 2 of 7	NP_001362573.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAA	ENST00000649156.2	MANE Select	c.397C>A	p.Gln133Lys	missense	Exon 2 of 7	ENSP00000497008.1
	MMAA	ENST00000511969.4	TSL:1	n.397C>A		non_coding_transcript_exon	Exon 1 of 5	ENSP00000427422.1
	MMAA	ENST00000541599.5	TSL:5	c.397C>A	p.Gln133Lys	missense	Exon 2 of 7	ENSP00000442284.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458984 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725398

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110444

Other (OTH) AF: 0.0000166 AC: 1 AN: 60254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.063
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.71	N
PhyloP100		7.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.29
Sift	Benign	0.67	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.53
MutPred		0.35		Loss of ubiquitination at K138 (P = 0.0304)
MVP		0.93
MPC		0.15
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.68
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs754545360; hg19: chr4-146560688;