rs61750442

chr2-149582194-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015702.3(MMADHC):c.87A>C(p.Lys29Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0094 in 1,613,984 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (89 hom.)
• Consequence: MMADHC NM_015702.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.25

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010101467).
• BP6: Variant 2-149582194-T-G is Benign according to our data. Variant chr2-149582194-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 331383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00739 (1126/152332) while in subpopulation NFE AF= 0.0105 (711/68032). AF 95% confidence interval is 0.00981. There are 5 homozygotes in gnomad4. There are 586 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMADHC	NM_015702.3	c.87A>C	p.Lys29Asn	missense_variant	3/8	ENST00000303319.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMADHC	ENST00000303319.10	c.87A>C	p.Lys29Asn	missense_variant	3/8	1	NM_015702.3	P1
MMADHC	ENST00000422782.2	c.87A>C	p.Lys29Asn	missense_variant	3/9	5
MMADHC	ENST00000428879.5	c.87A>C	p.Lys29Asn	missense_variant	2/7	2		P1

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1126 AN: 152214 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00850 AC: 2136 AN: 251312 Hom.: 13 AF XY: 0.00860 AC XY: 1168 AN XY: 135822

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00594

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00961 AC: 14053 AN: 1461652 Hom.: 89 Cov.: 31 AF XY: 0.00933 AC XY: 6781 AN XY: 727106

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00671

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00234

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00906

GnomAD4 genome AF: 0.00739 AC: 1126 AN: 152332 Hom.: 5 Cov.: 32 AF XY: 0.00787 AC XY: 586 AN XY: 74484

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00938 Hom.: 18

Bravo AF: 0.00660

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0113 AC: 97

ExAC AF: 0.00878 AC: 1066

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 22, 2019	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MMADHC: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2016

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T
Eigen	Benign	-0.089
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.14	B;B;B
Vest4		0.56
MutPred		0.61		Loss of methylation at K29 (P = 0.0406);Loss of methylation at K29 (P = 0.0406);Loss of methylation at K29 (P = 0.0406);
MVP		0.77
MPC		0.065
ClinPred		0.019	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs61750442; hg19: chr2-150438708;