2-149569810-T-C

Position:

• chr2-149569810-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015702.3(MMADHC):​c.*164A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 652,832 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0097 (61 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (75 hom.)
• Consequence: MMADHC NM_015702.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.00100

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-149569810-T-C is Benign according to our data. Variant chr2-149569810-T-C is described in ClinVar as [Benign]. Clinvar id is 331372.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMADHC	NM_015702.3	c.*164A>G		3_prime_UTR_variant	8/8	ENST00000303319.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMADHC	ENST00000303319.10	c.*164A>G		3_prime_UTR_variant	8/8	1	NM_015702.3	P1
MMADHC	ENST00000422782.2	c.*164A>G		3_prime_UTR_variant	9/9	5
MMADHC	ENST00000428879.5	c.*164A>G		3_prime_UTR_variant	7/7	2		P1

Frequencies

GnomAD3 genomes AF: 0.00969 AC: 1474 AN: 152182 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00481 AC: 2408 AN: 500532 Hom.: 75 Cov.: 6 AF XY: 0.00445 AC XY: 1171 AN XY: 263190

Gnomad4 AFR exome AF: 0.00543

Gnomad4 AMR exome AF: 0.0742

Gnomad4 ASJ exome AF: 0.000548

Gnomad4 EAS exome AF: 0.0000650

Gnomad4 SAS exome AF: 0.00288

Gnomad4 FIN exome AF: 0.0000307

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00692

GnomAD4 genome AF: 0.00967 AC: 1472 AN: 152300 Hom.: 61 Cov.: 33 AF XY: 0.0110 AC XY: 819 AN XY: 74464

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.0761

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00428 Hom.: 0

Bravo AF: 0.0148

Asia WGS AF: 0.00491 AC: 17 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Methylmalonic aciduria and homocystinuria type cblD Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs147662711; hg19: chr2-150426324;