chr2-149587299-C-T

Variant names:

• chr2-149587299-C-T
• rs4667419
• NM_015702.3:c.-52-150G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015702.3(MMADHC):​c.-52-150G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 619,970 control chromosomes in the GnomAD database, including 224,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (44451 hom., cov: 31)
  • Exomes 𝑓: 0.87 (179811 hom.)
• Consequence: MMADHC NM_015702.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.85
• Publications: 8 publications found

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]

MMADHC-DT (HGNC:41087): (MMADHC divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-149587299-C-T is Benign according to our data. Variant chr2-149587299-C-T is described in ClinVar as Benign. ClinVar VariationId is 1247490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015702.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMADHC	NM_015702.3	MANE Select	c.-52-150G>A		intron	N/A	NP_056517.1	Q9H3L0
	MMADHC-DT	NR_110240.1		n.-59C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMADHC	ENST00000303319.10	TSL:1 MANE Select	c.-52-150G>A		intron	N/A	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000428879.5	TSL:2	c.-202G>A		5_prime_UTR	Exon 1 of 7	ENSP00000389060.1	Q9H3L0
	MMADHC	ENST00000893997.1		c.-73G>A		5_prime_UTR	Exon 1 of 8	ENSP00000564056.1

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109492 AN: 151932 Hom.: 44446 Cov.: 31

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.897

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.896

Gnomad OTH AF: 0.754

GnomAD4 exome AF: 0.870 AC: 407109 AN: 467920 Hom.: 179811 Cov.: 4 AF XY: 0.875 AC XY: 218041 AN XY: 249246

African (AFR) AF: 0.321 AC: 4192 AN: 13076

American (AMR) AF: 0.736 AC: 16193 AN: 21992

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 12615 AN: 14234

East Asian (EAS) AF: 0.877 AC: 27353 AN: 31172

South Asian (SAS) AF: 0.900 AC: 43362 AN: 48166

European-Finnish (FIN) AF: 0.935 AC: 28686 AN: 30674

Middle Eastern (MID) AF: 0.864 AC: 3141 AN: 3636

European-Non Finnish (NFE) AF: 0.895 AC: 248982 AN: 278092

Other (OTH) AF: 0.840 AC: 22585 AN: 26878

GnomAD4 genome AF: 0.720 AC: 109511 AN: 152050 Hom.: 44451 Cov.: 31 AF XY: 0.726 AC XY: 53958 AN XY: 74332

African (AFR) AF: 0.318 AC: 13180 AN: 41428

American (AMR) AF: 0.718 AC: 10983 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3059 AN: 3468

East Asian (EAS) AF: 0.863 AC: 4439 AN: 5142

South Asian (SAS) AF: 0.898 AC: 4325 AN: 4814

European-Finnish (FIN) AF: 0.942 AC: 9993 AN: 10606

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.896 AC: 60889 AN: 67982

Other (OTH) AF: 0.755 AC: 1592 AN: 2110

Alfa AF: 0.805 Hom.: 68146

Bravo AF: 0.684

Asia WGS AF: 0.846 AC: 2939 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.9
DANN	Benign	0.90
PhyloP100		-1.9
PromoterAI		0.088	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs4667419; hg19: chr2-150443813; COSMIC: COSV57574702;