1-45500351-G-A

Position:

• chr1-45500351-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_015506.3(MMACHC):​c.19G>A​(p.Glu7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,178 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).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 49 pathogenic changes around while only 14 benign (78%) in NM_015506.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.093292326).
• BP6: Variant 1-45500351-G-A is Benign according to our data. Variant chr1-45500351-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 973438.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.19G>A	p.Glu7Lys	missense_variant	1/4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.-204G>A		5_prime_UTR_variant	1/4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.19G>A	p.Glu7Lys	missense_variant	1/4	2	NM_015506.3	ENSP00000383840.4
MMACHC	ENST00000616135	c.-153G>A		5_prime_UTR_variant	1/5	2		ENSP00000478859.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000601 AC: 15 AN: 249576 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135398

Gnomad AFR exome AF: 0.000774

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000205 AC: 30 AN: 1461828 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 727214

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152350 Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74504

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.000996 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000661 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cobalamin C disease Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.072	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.093	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.44
Sift	Benign	0.060	T
Sift4G	Benign	0.12	T
Polyphen		0.29	B
Vest4		0.21
MVP		0.95
MPC		0.012
ClinPred		0.070	T
GERP RS		5.8
Varity_R		0.39
gMVP		0.46

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: rs377405910; hg19: chr1-45966023;