1-236795531-G-T

Variant names:

• chr1-236795531-G-T
• rs3738548
• NM_000254.3:c.-173G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000254.3(MTR):​c.-173G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 1,530,536 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (7 hom.)
• Consequence: MTR NM_000254.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.21
• Publications: 1 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.023).
• BP6: Variant 1-236795531-G-T is Benign according to our data. Variant chr1-236795531-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 296540.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000263 (40/152346) while in subpopulation SAS AF = 0.0058 (28/4830). AF 95% confidence interval is 0.00412. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. 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.-173G>T		5_prime_UTR	Exon 1 of 33	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.-173G>T		5_prime_UTR	Exon 1 of 32	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.-173G>T		5_prime_UTR	Exon 1 of 31	NP_001397871.1	A0A7P0TAJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.-173G>T		5_prime_UTR	Exon 1 of 33	ENSP00000355536.5	Q99707-1
	MTR	ENST00000961801.1		c.-173G>T		5_prime_UTR	Exon 1 of 31	ENSP00000631860.1
	MTR	ENST00000905140.1		c.-173G>T		5_prime_UTR	Exon 1 of 32	ENSP00000575199.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00113 AC: 160 AN: 141910 AF XY: 0.00152

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000471

GnomAD4 exome AF: 0.000492 AC: 678 AN: 1378190 Hom.: 7 Cov.: 31 AF XY: 0.000692 AC XY: 471 AN XY: 680514

African (AFR) AF: 0.0000318 AC: 1 AN: 31450

American (AMR) AF: 0.000112 AC: 4 AN: 35594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24914

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35446

South Asian (SAS) AF: 0.00721 AC: 570 AN: 79076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33862

Middle Eastern (MID) AF: 0.00213 AC: 12 AN: 5646

European-Non Finnish (NFE) AF: 0.0000614 AC: 66 AN: 1074730

Other (OTH) AF: 0.000418 AC: 24 AN: 57472

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74488

African (AFR) AF: 0.0000481 AC: 2 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.46
PhyloP100		-1.2
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=295/5	polymorphism

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: rs3738548; hg19: chr1-236958831;