chr2-149587408-G-C

Variant names:

• chr2-149587408-G-C
• rs114193203
• NM_015702.3:c.-53+256C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015702.3(MMADHC):​c.-53+256C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 481,602 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0099 (22 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: MMADHC NM_015702.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.31
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-149587408-G-C is Benign according to our data. Variant chr2-149587408-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1216481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00987 (1504/152338) while in subpopulation AFR AF = 0.0346 (1440/41576). AF 95% confidence interval is 0.0331. There are 22 homozygotes in GnomAd4. There are 719 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.-53+256C>G		intron	N/A	NP_056517.1	Q9H3L0
	MMADHC-DT	NR_110240.1		n.51G>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.-53+256C>G		intron	N/A	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000428879.5	TSL:2	c.-311C>G		5_prime_UTR	Exon 1 of 7	ENSP00000389060.1	Q9H3L0
	MMADHC	ENST00000934249.1		c.-53+256C>G		intron	N/A	ENSP00000604308.1

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152220 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

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: 0.000132

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00130 AC: 429 AN: 329264 Hom.: 6 Cov.: 0 AF XY: 0.00108 AC XY: 187 AN XY: 173412

African (AFR) AF: 0.0324 AC: 329 AN: 10142

American (AMR) AF: 0.00247 AC: 31 AN: 12562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10230

East Asian (EAS) AF: 0.00 AC: 0 AN: 21846

South Asian (SAS) AF: 0.0000837 AC: 3 AN: 35862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19246

Middle Eastern (MID) AF: 0.00132 AC: 2 AN: 1510

European-Non Finnish (NFE) AF: 0.000101 AC: 20 AN: 198390

Other (OTH) AF: 0.00226 AC: 44 AN: 19476

GnomAD4 genome AF: 0.00987 AC: 1504 AN: 152338 Hom.: 22 Cov.: 31 AF XY: 0.00965 AC XY: 719 AN XY: 74502

African (AFR) AF: 0.0346 AC: 1440 AN: 41576

American (AMR) AF: 0.00300 AC: 46 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00846 Hom.: 1

Bravo AF: 0.0120

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.75
PhyloP100		-1.3
PromoterAI		-0.16	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114193203; hg19: chr2-150443922;