rs61750442

Variant names:

• chr2-149582194-T-G
• rs61750442
• NM_015702.3:c.87A>C

Variant summary

Our verdict is Benign. The variant received -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:10
• Conservation: PhyloP100: 1.25
• Publications: 9 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 -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.87A>C	p.Lys29Asn	missense	Exon 3 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.87A>C	p.Lys29Asn	missense	Exon 3 of 8	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000934249.1		c.87A>C	p.Lys29Asn	missense	Exon 3 of 9	ENSP00000604308.1
	MMADHC	ENST00000422782.2	TSL:5	c.87A>C	p.Lys29Asn	missense	Exon 3 of 9	ENSP00000408331.2	F8WEC0

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

GnomAD2 exomes AF: 0.00850 AC: 2136 AN: 251312 AF XY: 0.00860

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 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

African (AFR) AF: 0.00179 AC: 60 AN: 33472

American (AMR) AF: 0.00671 AC: 300 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00234 AC: 202 AN: 86248

European-Finnish (FIN) AF: 0.0176 AC: 938 AN: 53410

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5764

European-Non Finnish (NFE) AF: 0.0107 AC: 11928 AN: 1111870

Other (OTH) AF: 0.00906 AC: 547 AN: 60386

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

African (AFR) AF: 0.00188 AC: 78 AN: 41590

American (AMR) AF: 0.00811 AC: 124 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 711 AN: 68032

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00932 Hom.: 37

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.089
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.14	B
Vest4		0.56
MutPred		0.61		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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs61750442; hg19: chr2-150438708;