rs1057520160

Positions:

• chr4-145655319-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172250.3(MMAA):​c.1142C>T​(p.Thr381Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MMAA NM_172250.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19999638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAA	NM_172250.3	c.1142C>T	p.Thr381Ile	missense_variant	7/7	ENST00000649156.2
MMAA	NM_001375644.1	c.1142C>T	p.Thr381Ile	missense_variant	7/7
MMAA	XM_011531684.4	c.1142C>T	p.Thr381Ile	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAA	ENST00000649156.2	c.1142C>T	p.Thr381Ile	missense_variant	7/7		NM_172250.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblA type Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 19, 2022	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 381 of the MMAA protein (p.Thr381Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MMAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 377200). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MMAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 04, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 23, 2022	The MMAA c.1142C>T (p.Thr381Ile) missense variant results in the substitution of threonine at amino acid position 381 with isoleucine. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.1142C>T (p.Thr381Ile) variant is classified as a variant of uncertain significance for methylmalonic aciduria, cblA type. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2021

The c.1142C>T (p.T381I) alteration is located in exon 7 (coding exon 6) of the MMAA gene. This alteration results from a C to T substitution at nucleotide position 1142, causing the threonine (T) at amino acid position 381 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;D;D;D;D
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.58	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.6	L;.;L;L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
Polyphen		0.16	B;.;B;B;B;.
Vest4		0.16, 0.20
MutPred		0.55		Gain of catalytic residue at P383 (P = 0.0393);.;Gain of catalytic residue at P383 (P = 0.0393);Gain of catalytic residue at P383 (P = 0.0393);Gain of catalytic residue at P383 (P = 0.0393);Gain of catalytic residue at P383 (P = 0.0393);
MVP		0.82
MPC		0.19
ClinPred		0.46	T
GERP RS		-1.1
Varity_R		0.14
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057520160; hg19: chr4-146576471;