2-149576462-C-T

Position:

• chr2-149576462-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 203836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-149576462-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.453G>A	p.Gln151Gln	synonymous_variant	5/8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.453G>A	p.Gln151Gln	synonymous_variant	5/8	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.453G>A	p.Gln151Gln	synonymous_variant	5/9	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.453G>A	p.Gln151Gln	synonymous_variant	4/7	2		ENSP00000389060.1

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

GnomAD3 exomes AF: 0.873 AC: 219524 AN: 251342 Hom.: 97163 AF XY: 0.882 AC XY: 119857 AN XY: 135844

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 SAS exome AF: 0.902

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

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.842

Gnomad4 ASJ exome AF: 0.894

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.905

Gnomad4 FIN exome AF: 0.942

Gnomad4 NFE exome AF: 0.909

Gnomad4 OTH exome AF: 0.882

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

Gnomad4 AFR AF: 0.516

Gnomad4 AMR AF: 0.827

Gnomad4 ASJ AF: 0.889

Gnomad4 EAS AF: 0.864

Gnomad4 SAS AF: 0.905

Gnomad4 FIN AF: 0.947

Gnomad4 NFE AF: 0.913

Gnomad4 OTH AF: 0.828

Alfa AF: 0.863 Hom.: 27452

Bravo AF: 0.771

Asia WGS AF: 0.869 AC: 3020 AN: 3478

EpiCase AF: 0.909

EpiControl AF: 0.902

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 87% of total chromosomes in ExAC -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	1.8
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

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