2-149587408-G-C

Position:

• chr2-149587408-G-C

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.-53+256C>G		intron_variant		ENST00000303319.10	NP_056517.1
MMADHC-DT	NR_110240.1	n.51G>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.-53+256C>G		intron_variant		1	NM_015702.3	ENSP00000301920	P1

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

Gnomad4 AFR exome AF: 0.0324

Gnomad4 AMR exome AF: 0.00247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000837

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00226

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

Gnomad4 AFR AF: 0.0346

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00846 Hom.: 1

Bravo AF: 0.0120

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs114193203; hg19: chr2-150443922;