chr2-149576462-C-T

Variant names:

• chr2-149576462-C-T
• rs11545261
• NM_015702.3:c.453G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015702.3(MMADHC):​c.453G>A​(p.Gln151Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.887 in 1,611,946 control chromosomes in the GnomAD database, including 639,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (50343 hom., cov: 32)
  • Exomes 𝑓: 0.90 (589374 hom.)
• Consequence: MMADHC NM_015702.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0920
• Publications: 25 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 Gene-Disease associations (from GenCC):

• inborn disorder of cobalamin metabolism and transport

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• methylmalonic aciduria and homocystinuria type cblD

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 2-149576462-C-T is Benign according to our data. Variant chr2-149576462-C-T is described in ClinVar as Benign. ClinVar VariationId is 203836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.907 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.453G>A	p.Gln151Gln	synonymous	Exon 5 of 8	NP_056517.1	Q9H3L0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMADHC	ENST00000303319.10	TSL:1 MANE Select	c.453G>A	p.Gln151Gln	synonymous	Exon 5 of 8	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000934249.1		c.576G>A	p.Gln192Gln	synonymous	Exon 6 of 9	ENSP00000604308.1
	MMADHC	ENST00000422782.2	TSL:5	c.453G>A	p.Gln151Gln	synonymous	Exon 5 of 9	ENSP00000408331.2	F8WEC0

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120877 AN: 152000 Hom.: 50330 Cov.: 32

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.903

Gnomad FIN AF: 0.947

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.828

GnomAD2 exomes AF: 0.873 AC: 219524 AN: 251342 AF XY: 0.882

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.847

Gnomad ASJ exome AF: 0.901

Gnomad EAS exome AF: 0.863

Gnomad FIN exome AF: 0.943

Gnomad NFE exome AF: 0.911

Gnomad OTH exome AF: 0.884

GnomAD4 exome AF: 0.896 AC: 1308164 AN: 1459828 Hom.: 589374 Cov.: 38 AF XY: 0.898 AC XY: 652192 AN XY: 726390

African (AFR) AF: 0.495 AC: 16538 AN: 33384

American (AMR) AF: 0.842 AC: 37643 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 23356 AN: 26112

East Asian (EAS) AF: 0.875 AC: 34632 AN: 39602

South Asian (SAS) AF: 0.905 AC: 78051 AN: 86232

European-Finnish (FIN) AF: 0.942 AC: 50286 AN: 53406

Middle Eastern (MID) AF: 0.895 AC: 5156 AN: 5762

European-Non Finnish (NFE) AF: 0.909 AC: 1009282 AN: 1110310

Other (OTH) AF: 0.882 AC: 53220 AN: 60308

GnomAD4 genome AF: 0.795 AC: 120929 AN: 152118 Hom.: 50343 Cov.: 32 AF XY: 0.799 AC XY: 59388 AN XY: 74370

African (AFR) AF: 0.516 AC: 21386 AN: 41440

American (AMR) AF: 0.827 AC: 12635 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3088 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4470 AN: 5174

South Asian (SAS) AF: 0.905 AC: 4361 AN: 4820

European-Finnish (FIN) AF: 0.947 AC: 10046 AN: 10604

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.913 AC: 62090 AN: 68004

Other (OTH) AF: 0.828 AC: 1751 AN: 2116

Alfa AF: 0.858 Hom.: 36913

Bravo AF: 0.771

Asia WGS AF: 0.869 AC: 3020 AN: 3478

EpiCase AF: 0.909

EpiControl AF: 0.902

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Methylmalonic aciduria and homocystinuria type cblD (5)
-	-	4	not specified (4)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		-0.092
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs11545261; hg19: chr2-150432976; COSMIC: COSV57574188;