rs118204046

Variant names:

• chr2-149570119-T-A
• NM_015702.3:c.746A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-149570119-T-A
• chr2-149570119-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_015702.3(MMADHC):​c.746A>T​(p.Tyr249Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. Y249C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MMADHC NM_015702.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.03

Genes affected

MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-149570119-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.33113497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.746A>T	p.Tyr249Phe	missense_variant	Exon 8 of 8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.746A>T	p.Tyr249Phe	missense_variant	Exon 8 of 8	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.848A>T	p.Tyr283Phe	missense_variant	Exon 9 of 9	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.746A>T	p.Tyr249Phe	missense_variant	Exon 7 of 7	2		ENSP00000389060.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461616 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727106

Gnomad4 AFR exome AF: 0.0000896

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	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.51	P;P;P
Vest4		0.39
MutPred		0.67		.;.;Gain of helix (P = 0.1736);
MVP		0.60
MPC		0.14
ClinPred		0.78	D
GERP RS		5.0
Varity_R		0.44
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-150426633;