rs35219601

Positions:

• chr1-45509177-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_015506.3(MMACHC):​c.811A>G​(p.Ser271Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,613,884 control chromosomes in the GnomAD database, including 1,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S271S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (566 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (501 hom.)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.32

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 Benign. Variant got -18 ACMG points.

• PM1: In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 50 pathogenic changes around while only 14 benign (78%) in NM_015506.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017081201).
• BP6: Variant 1-45509177-A-G is Benign according to our data. Variant chr1-45509177-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45509177-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3	c.811A>G	p.Ser271Gly	missense_variant	4/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.640A>G	p.Ser214Gly	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.811A>G	p.Ser271Gly	missense_variant	4/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1	c.640A>G	p.Ser214Gly	missense_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6942 AN: 151994 Hom.: 567 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0112 AC: 2798 AN: 249008 Hom.: 204 AF XY: 0.00865 AC XY: 1169 AN XY: 135190

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.00763

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00613

GnomAD4 exome AF: 0.00468 AC: 6838 AN: 1461772 Hom.: 501 Cov.: 32 AF XY: 0.00401 AC XY: 2913 AN XY: 727192

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.00879

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0457 AC: 6949 AN: 152112 Hom.: 566 Cov.: 32 AF XY: 0.0449 AC XY: 3343 AN XY: 74392

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0337

Alfa AF: 0.0144 Hom.: 151

Bravo AF: 0.0515

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.142 AC: 529

ESP6500EA AF: 0.000366 AC: 3

ExAC AF: 0.0134 AC: 1614

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 27, 2020	Variant summary: MMACHC c.811A>G (p.Ser271Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.015 in 280360 control chromosomes, predominantly at a frequency of 0.16 within the African or African-American subpopulation in the gnomAD database, including 323 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 53 fold of the estimated maximal expected allele frequency for a pathogenic variant in MMACHC causing Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cobalamin C disease Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.080	N;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.059	T;T
Polyphen		0.0	B;.
Vest4		0.11
MPC		0.011
ClinPred		0.064	T
GERP RS		2.6
Varity_R		0.11
gMVP		0.44

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: rs35219601; hg19: chr1-45974849;