rs34702224

Positions:

• chr4-145639277-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_172250.3(MMAA):​c.138T>C​(p.Ser46Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,202 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (42 hom.)
• Consequence: MMAA NM_172250.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00300

Genes affected

MMAA (HGNC:18871): (metabolism of cobalamin associated A) The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMAA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-145639277-T-C is Benign according to our data. Variant chr4-145639277-T-C is described in ClinVar as [Benign]. Clinvar id is 262806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.003 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1716/152322) while in subpopulation AFR AF= 0.0381 (1585/41574). AF 95% confidence interval is 0.0366. There are 29 homozygotes in gnomad4. There are 778 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMAA	NM_172250.3	c.138T>C	p.Ser46Ser	synonymous_variant	2/7	ENST00000649156.2	NP_758454.1
MMAA	NM_001375644.1	c.138T>C	p.Ser46Ser	synonymous_variant	2/7		NP_001362573.1
MMAA	XM_011531684.4	c.138T>C	p.Ser46Ser	synonymous_variant	2/7		XP_011529986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2	c.138T>C	p.Ser46Ser	synonymous_variant	2/7		NM_172250.3	ENSP00000497008.1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1715 AN: 152204 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00318 AC: 800 AN: 251452 Hom.: 9 AF XY: 0.00249 AC XY: 339 AN XY: 135898

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00159 AC: 2330 AN: 1461880 Hom.: 42 Cov.: 32 AF XY: 0.00150 AC XY: 1090 AN XY: 727240

Gnomad4 AFR exome AF: 0.0440

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00758

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.0113 AC: 1716 AN: 152322 Hom.: 29 Cov.: 33 AF XY: 0.0104 AC XY: 778 AN XY: 74500

Gnomad4 AFR AF: 0.0381

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00607 Hom.: 14

Bravo AF: 0.0125

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblA type Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.8
DANN	Benign	0.63

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: rs34702224; hg19: chr4-146560429;