2-149587756-T-C

Position:

• chr2-149587756-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015702.3(MMADHC):​c.-145A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 152,982 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 0.014 (28 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (0 hom.)
• Consequence: MMADHC NM_015702.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.18

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-149587756-T-C is Benign according to our data. Variant chr2-149587756-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 331390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2118/152308) while in subpopulation AFR AF= 0.0165 (687/41578). AF 95% confidence interval is 0.0155. There are 28 homozygotes in gnomad4. There are 976 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.-145A>G		5_prime_UTR_variant	1/8	ENST00000303319.10	NP_056517.1
MMADHC-DT	NR_110240.1	n.399T>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.-145A>G		5_prime_UTR_variant	1/8	1	NM_015702.3	ENSP00000301920.5

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2118 AN: 152190 Hom.: 28 Cov.: 31

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.00742 AC: 5 AN: 674 Hom.: 0 Cov.: 0 AF XY: 0.00532 AC XY: 2 AN XY: 376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00948

Gnomad4 OTH exome AF: 0.0357

GnomAD4 genome AF: 0.0139 AC: 2118 AN: 152308 Hom.: 28 Cov.: 31 AF XY: 0.0131 AC XY: 976 AN XY: 74482

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0109 Hom.: 9

Bravo AF: 0.0150

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0030
DANN	Benign	0.43
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: rs12477482; hg19: chr2-150444270;