rs13402787

Variant names:

• chr2-149576431-A-C
• rs13402787
• NM_015702.3:c.478+6T>G

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.478+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,576,222 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (58 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (64 hom.)
• Consequence: MMADHC NM_015702.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004755
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.00
• Publications: 3 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 (BayesDel_noAF=-0.82).
• BP6: Variant 2-149576431-A-C is Benign according to our data. Variant chr2-149576431-A-C is described in ClinVar as Benign. ClinVar VariationId is 331378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0507 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.478+6T>G		splice_region intron	N/A	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.478+6T>G		splice_region intron	N/A	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000934249.1		c.601+6T>G		splice_region intron	N/A	ENSP00000604308.1
	MMADHC	ENST00000422782.2	TSL:5	c.478+6T>G		splice_region intron	N/A	ENSP00000408331.2	F8WEC0

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2295 AN: 152168 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00392 AC: 986 AN: 251286 AF XY: 0.00283

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00158 AC: 2255 AN: 1423936 Hom.: 64 Cov.: 24 AF XY: 0.00134 AC XY: 956 AN XY: 711002

African (AFR) AF: 0.0548 AC: 1799 AN: 32824

American (AMR) AF: 0.00318 AC: 142 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39422

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00281 AC: 16 AN: 5688

European-Non Finnish (NFE) AF: 0.0000622 AC: 67 AN: 1077462

Other (OTH) AF: 0.00376 AC: 222 AN: 59108

GnomAD4 genome AF: 0.0152 AC: 2315 AN: 152286 Hom.: 58 Cov.: 32 AF XY: 0.0147 AC XY: 1098 AN XY: 74460

African (AFR) AF: 0.0525 AC: 2181 AN: 41554

American (AMR) AF: 0.00615 AC: 94 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68016

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00764 Hom.: 25

Bravo AF: 0.0178

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Methylmalonic aciduria and homocystinuria type cblD (3)
-	-	3	not provided (3)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.1
DANN	Benign	0.62
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.036
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: rs13402787; hg19: chr2-150432945;