Variant 2-149569848-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.41

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
MMADHC	NM_015702.3 linkuse as main transcript	c.*126A>G		3_prime_UTR_variant	8/8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris
MMADHC	ENST00000303319.10 linkuse as main transcript	c.*126A>G	3_prime_UTR_variant	8/8	1	NM_015702.3	ENSP00000301920	P1
MMADHC	ENST00000422782.2 linkuse as main transcript	c.*126A>G	3_prime_UTR_variant	9/9	5		ENSP00000408331
MMADHC	ENST00000428879.5 linkuse as main transcript	c.*126A>G	3_prime_UTR_variant	7/7	2		ENSP00000389060	P1

Frequencies

GnomAD3 genomes

AF:

0.505

AC:

76842

AN:

152030

Hom.:

21389

Cov.:

show subpopulations

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.:

AF XY:

0.602

AC XY:

235656

AN XY:

391200

show subpopulations

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.:

AF XY:

0.512

AC XY:

38108

AN XY:

74366

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

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. -

Methylmalonic aciduria and homocystinuria type cblD

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over