2-149569848-T-C

Position:

• chr2-149569848-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015702.3(MMADHC):​c.*126A>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 0.584 in 916,652 control chromosomes in the GnomAD database, including 161,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21403 hom., cov: 34)
  • Exomes 𝑓: 0.60 (140040 hom.)
• Consequence: MMADHC NM_015702.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.41

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-149569848-T-C is Benign according to our data. Variant chr2-149569848-T-C is described in ClinVar as [Benign]. Clinvar id is 331373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMADHC	NM_015702.3	c.*126A>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.*126A>G		3_prime_UTR_variant	8/8	1	NM_015702.3	P1
MMADHC	ENST00000422782.2	c.*126A>G		3_prime_UTR_variant	9/9	5
MMADHC	ENST00000428879.5	c.*126A>G		3_prime_UTR_variant	7/7	2		P1

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76842 AN: 152030 Hom.: 21389 Cov.: 34

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.547

GnomAD4 exome AF: 0.600 AC: 458397 AN: 764504 Hom.: 140040 Cov.: 10 AF XY: 0.602 AC XY: 235656 AN XY: 391200

Gnomad4 AFR exome AF: 0.259

Gnomad4 AMR exome AF: 0.548

Gnomad4 ASJ exome AF: 0.689

Gnomad4 EAS exome AF: 0.876

Gnomad4 SAS exome AF: 0.666

Gnomad4 FIN exome AF: 0.641

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.599

GnomAD4 genome AF: 0.505 AC: 76867 AN: 152148 Hom.: 21403 Cov.: 34 AF XY: 0.512 AC XY: 38108 AN XY: 74366

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.525

Gnomad4 ASJ AF: 0.673

Gnomad4 EAS AF: 0.855

Gnomad4 SAS AF: 0.686

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.578

Gnomad4 OTH AF: 0.550

Alfa AF: 0.533 Hom.: 3096

Bravo AF: 0.488

Asia WGS AF: 0.751 AC: 2608 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Methylmalonic aciduria and homocystinuria type cblD Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.70
CADD	Benign	13
DANN	Benign	0.83
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: rs6923; hg19: chr2-150426362; COSMIC: COSV57574660;