chr1-236825371-C-T

Variant names:

• chr1-236825371-C-T
• rs201871910
• NM_000254.3:c.899C>T

Variant summary

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

The NM_001291940.2(MTR):​c.-210C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000768 in 1,613,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: MTR NM_001291940.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.06
• Publications: 3 publications found

Genes affected

MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

MTR Gene-Disease associations (from GenCC):

• methylcobalamin deficiency type cblG

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291940.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.899C>T	p.Thr300Met	missense	Exon 10 of 33	NP_000245.2
	MTR	NM_001291940.2		c.-210C>T		5_prime_UTR_premature_start_codon_gain	Exon 10 of 32	NP_001278869.1
	MTR	NM_001291939.1		c.899C>T	p.Thr300Met	missense	Exon 10 of 32	NP_001278868.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.899C>T	p.Thr300Met	missense	Exon 10 of 33	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.899C>T	p.Thr300Met	missense	Exon 10 of 32	ENSP00000441845.1
	MTR	ENST00000681102.1		c.899C>T	p.Thr300Met	missense	Exon 10 of 32	ENSP00000505600.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152044 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251450 AF XY: 0.0000883

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000828 AC: 121 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.0000798 AC XY: 58 AN XY: 727116

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000917 AC: 102 AN: 1111730

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152044 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74276

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Methylcobalamin deficiency type cblG (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.67
MPC		1.2
ClinPred		0.91	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.86
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201871910; hg19: chr1-236988671;