chr4-145639140-A-G

Variant names:

• chr4-145639140-A-G
• rs1553957856
• NM_172250.3:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_172250.3(MMAA):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMAA NM_172250.3 start_lost
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.467
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• methylmalonic aciduria, cblA type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 3 codons. Genomic position: 145639146. Lost 0.006 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-145639140-A-G is Pathogenic according to our data. Variant chr4-145639140-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551711.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAA	NM_172250.3	c.1A>G	p.Met1?	start_lost	Exon 2 of 7	ENST00000649156.2	NP_758454.1
MMAA	NM_001375644.1	c.1A>G	p.Met1?	start_lost	Exon 2 of 7		NP_001362573.1
MMAA	XM_011531684.4	c.1A>G	p.Met1?	start_lost	Exon 2 of 7		XP_011529986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2	c.1A>G	p.Met1?	start_lost	Exon 2 of 7		NM_172250.3	ENSP00000497008.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Methylmalonic aciduria, cblA type Pathogenic:1

May 04, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.3
DANN	Benign	0.64
DEOGEN2	Benign	0.15	T;.;T;T;T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.051	N
LIST_S2	Uncertain	0.90	.;D;.;.;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
PhyloP100		0.47
PROVEAN	Benign	0.020	.;.;N;.;.;N
REVEL	Benign	0.11
Sift	Benign	0.32	.;.;T;.;.;T
Sift4G	Benign	1.0	.;.;T;.;.;T
Polyphen		0.0	B;.;B;B;B;.
Vest4		0.13, 0.17
MutPred		0.67		Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);Loss of glycosylation at P2 (P = 0.0555);
MVP		0.38
ClinPred		0.14	T
GERP RS		1.1
Varity_R		0.042
gMVP		0.50
Mutation Taster		=167/33	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553957856; hg19: chr4-146560292;