2-149587666-G-C

Variant names:

• chr2-149587666-G-C
• rs988301282
• NM_015702.3:c.-55C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP3_Moderate BP6_Moderate BS1

The NM_015702.3(MMADHC):​c.-55C>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 152,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MMADHC NM_015702.3 splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.193
• Publications: 0 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-DT (HGNC:41087): (MMADHC divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-149587666-G-C is Benign according to our data. Variant chr2-149587666-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 385796.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000151 (23/152204) while in subpopulation AFR AF = 0.000555 (23/41466). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.-55C>G		splice_region	Exon 1 of 8	NP_056517.1	Q9H3L0
	MMADHC	NM_015702.3	MANE Select	c.-55C>G		5_prime_UTR	Exon 1 of 8	NP_056517.1	Q9H3L0
	MMADHC-DT	NR_110240.1		n.309G>C		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMADHC	ENST00000303319.10	TSL:1 MANE Select	c.-55C>G		splice_region	Exon 1 of 8	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000303319.10	TSL:1 MANE Select	c.-55C>G		5_prime_UTR	Exon 1 of 8	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000934249.1		c.-55C>G		splice_region	Exon 1 of 9	ENSP00000604308.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 5190 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2996

African (AFR) AF: 0.00 AC: 0 AN: 56

American (AMR) AF: 0.00 AC: 0 AN: 1026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 46

East Asian (EAS) AF: 0.00 AC: 0 AN: 174

South Asian (SAS) AF: 0.00 AC: 0 AN: 1040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 56

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2572

Other (OTH) AF: 0.00 AC: 0 AN: 210

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74360

African (AFR) AF: 0.000555 AC: 23 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000117

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Benign	0.79
PhyloP100		0.19
PromoterAI		0.61	Over-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 5
DS_DL_spliceai		0.29		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs988301282; hg19: chr2-150444180;