1-45509214-G-C

Variant names:

• chr1-45509214-G-C
• rs201025783
• NM_015506.3:c.848G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_015506.3(MMACHC):​c.848G>C​(p.Ter283Serext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,613,932 control chromosomes in the GnomAD database, including 1 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 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: MMACHC NM_015506.3 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 1.35
• Publications: 8 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Stoplost variant in NM_015506.3 Downstream stopcodon found after 293 codons.

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>C	p.Ter283Serext*?	stop_lost	Exon 4 of 4	NP_056321.2	Q9Y4U1
	MMACHC	NM_001330540.2		c.677G>C	p.Ter226Serext*?	stop_lost	Exon 4 of 4	NP_001317469.1	A0A0C4DGU2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMACHC	ENST00000401061.9	TSL:2 MANE Select	c.848G>C	p.Ter283Serext*?	stop_lost	Exon 4 of 4	ENSP00000383840.4	Q9Y4U1
	MMACHC	ENST00000616135.1	TSL:2	c.677G>C	p.Ter226Serext*?	stop_lost	Exon 4 of 5	ENSP00000478859.1	A0A0C4DGU2
	MMACHC	ENST00000933807.1		c.653G>C	p.Ter218Serext*?	stop_lost	Exon 3 of 3	ENSP00000603866.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000258 AC: 64 AN: 248412 AF XY: 0.000319

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000365

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000235 AC: 344 AN: 1461788 Hom.: 1 Cov.: 32 AF XY: 0.000263 AC XY: 191 AN XY: 727190

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000217 AC: 241 AN: 1112006

Other (OTH) AF: 0.000282 AC: 17 AN: 60388

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41510

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68002

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000109 Hom.: 2

Bravo AF: 0.000170

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.000366 AC: 3

ExAC AF: 0.000430 AC: 52

EpiCase AF: 0.00125

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	Cobalamin C disease (5)
-	2	-	not provided (2)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	1	-	Methylmalonic acidemia with homocystinuria cblC (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.74
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		1.4
Vest4		0.082
GERP RS		3.5
Mutation Taster		=57/143	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201025783; hg19: chr1-45974886;