rs34702224

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.00300

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MMAA	NM_172250.3 link	c.138T>C	p.Ser46Ser	synonymous_variant	Exon 2 of 7	ENST00000649156.2	NP_758454.1	Q8IVH4
MMAA	NM_001375644.1 link	c.138T>C	p.Ser46Ser	synonymous_variant	Exon 2 of 7		NP_001362573.1
MMAA	XM_011531684.4 link	c.138T>C	p.Ser46Ser	synonymous_variant	Exon 2 of 7		XP_011529986.1	Q8IVH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 link	c.138T>C	p.Ser46Ser	synonymous_variant	Exon 2 of 7		NM_172250.3	ENSP00000497008.1		Q8IVH4

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1715

AN:

152204

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00249

AC XY:

339

AN XY:

135898

show subpopulations

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.:

Cov.:

AF XY:

0.00150

AC XY:

1090

AN XY:

727240

show subpopulations

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.:

Cov.:

AF XY:

0.0104

AC XY:

778

AN XY:

74500

show subpopulations

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.:

Bravo

AF:

0.0125

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Benign:3

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 30, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over