NM_015506.3:c.81G>A

Variant names:

• chr1-45500413-G-A
• rs1553162317
• NM_015506.3:c.81G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_015506.3(MMACHC):​c.81G>A​(p.Gln27Gln) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMACHC NM_015506.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.10
• Publications: 0 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]

CCDC163 (HGNC:27003): (CCDC163 homolog) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 1-45500413-G-A is Pathogenic according to our data. Variant chr1-45500413-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 495215.Status of the report is no_assertion_criteria_provided, 0 stars.

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.81G>A	p.Gln27Gln	splice_region synonymous	Exon 1 of 4	NP_056321.2	Q9Y4U1
	MMACHC	NM_001330540.2		c.-142G>A		splice_region	Exon 1 of 4	NP_001317469.1	A0A0C4DGU2
	MMACHC	NM_001330540.2		c.-142G>A		5_prime_UTR	Exon 1 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.81G>A	p.Gln27Gln	splice_region synonymous	Exon 1 of 4	ENSP00000383840.4	Q9Y4U1
	MMACHC	ENST00000616135.1	TSL:2	c.-91G>A		splice_region	Exon 1 of 5	ENSP00000478859.1	A0A0C4DGU2
	MMACHC	ENST00000933807.1		c.81G>A	p.Gln27Gln	splice_region synonymous	Exon 1 of 3	ENSP00000603866.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	26
DANN	Benign	0.95
PhyloP100		6.1
PromoterAI		-0.70	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: -15

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

Other links and lift over

dbSNP: rs1553162317; hg19: chr1-45966085;