rs115186224

Variant names:

• chr1-236831958-C-T
• rs115186224
• NM_000254.3:c.1076-8C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000254.3(MTR):​c.1076-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,611,136 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (24 hom.)
• Consequence: MTR NM_000254.3 splice_region, intron
• Scores: Splicing: ADA: 0.001340
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.610
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 1-236831958-C-T is Benign according to our data. Variant chr1-236831958-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00311 (474/152302) while in subpopulation NFE AF = 0.00548 (373/68030). AF 95% confidence interval is 0.00502. There are 2 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1076-8C>T		splice_region intron	N/A	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.1076-8C>T		splice_region intron	N/A	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.1076-8C>T		splice_region intron	N/A	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.1076-8C>T		splice_region intron	N/A	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.1076-8C>T		splice_region intron	N/A	ENSP00000441845.1	Q99707-2
	MTR	ENST00000681102.1		c.1076-8C>T		splice_region intron	N/A	ENSP00000505600.1	A0A7P0T9G7

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152184 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00548

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00259 AC: 651 AN: 251180 AF XY: 0.00243

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00385 AC: 5619 AN: 1458834 Hom.: 24 Cov.: 30 AF XY: 0.00377 AC XY: 2733 AN XY: 725896

African (AFR) AF: 0.000629 AC: 21 AN: 33408

American (AMR) AF: 0.00136 AC: 61 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 55 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86194

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53388

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.00471 AC: 5226 AN: 1109276

Other (OTH) AF: 0.00272 AC: 164 AN: 60302

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152302 Hom.: 2 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74482

African (AFR) AF: 0.000650 AC: 27 AN: 41552

American (AMR) AF: 0.00353 AC: 54 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00548 AC: 373 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00370 Hom.: 2

Bravo AF: 0.00280

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	Methylcobalamin deficiency type cblG (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.15		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: rs115186224; hg19: chr1-236995258;