chr1-45509214-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_015506.3(MMACHC):c.848G>T(p.Ter283Leuext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,613,930 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 4 hom. )

Consequence

MMACHC
NM_015506.3 stop_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 1.35

Publications

8 publications found

Variant links:

Genes affected

MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

MMACHC Gene-Disease associations (from GenCC):

methylmalonic aciduria and homocystinuria type cblC
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health

MMACHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM4

Stoplost variant in NM_015506.3 Downstream stopcodon found after 293 codons.

BP6

Variant 1-45509214-G-T is Benign according to our data. Variant chr1-45509214-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197306.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000224 (328/1461786) while in subpopulation AMR AF = 0.00727 (325/44720). AF 95% confidence interval is 0.00662. There are 4 homozygotes in GnomAdExome4. There are 114 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015506.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMACHC	NM_015506.3	MANE Select	c.848G>T	p.Ter283Leuext*?	stop_lost	Exon 4 of 4	NP_056321.2	Q9Y4U1
	MMACHC	NM_001330540.2		c.677G>T	p.Ter226Leuext*?	stop_lost	Exon 4 of 4	NP_001317469.1	A0A0C4DGU2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMACHC	ENST00000401061.9	TSL:2 MANE Select	c.848G>T	p.Ter283Leuext*?	stop_lost	Exon 4 of 4	ENSP00000383840.4	Q9Y4U1
MMACHC	ENST00000616135.1	TSL:2	c.677G>T	p.Ter226Leuext*?	stop_lost	Exon 4 of 5	ENSP00000478859.1	A0A0C4DGU2
MMACHC	ENST00000933807.1		c.653G>T	p.Ter218Leuext*?	stop_lost	Exon 3 of 3	ENSP00000603866.1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00112

AC:

277

AN:

248412

AF XY:

0.000756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00803

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000224

AC:

328

AN:

1461786

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00727

AC:

325

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000289

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41510

American (AMR)

AF:

0.00275

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.000661

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000770

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cobalamin C disease (4)

not provided (2)

Methylmalonic acidemia with homocystinuria cblC (1)

MMACHC-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.76

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.82

PhyloP100

1.4

Vest4

0.082

GERP RS

3.5

Mutation Taster

=137/63

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over