Genetic Variant NM_000254.3:c.-111C>T (chr1-236795593-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000254.3(MTR):c.-111C>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 0.00143 in 1,596,028 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 17 hom. )

Consequence

MTR
NM_000254.3 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.417

Publications

0 publications found

Variant links:

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

MTR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 1-236795593-C-T is Benign according to our data. Variant chr1-236795593-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00769 (1171/152362) while in subpopulation AFR AF = 0.0267 (1112/41590). AF 95% confidence interval is 0.0254. There are 15 homozygotes in GnomAd4. There are 533 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTR	NM_000254.3	MANE Select	c.-111C>T	5_prime_UTR	Exon 1 of 33	NP_000245.2	Q99707-1
MTR	NM_001291939.1		c.-111C>T	5_prime_UTR	Exon 1 of 32	NP_001278868.1	Q99707-2
MTR	NM_001410942.1		c.-111C>T	5_prime_UTR	Exon 1 of 31	NP_001397871.1	A0A7P0TAJ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTR	ENST00000366577.10	TSL:1 MANE Select	c.-111C>T	5_prime_UTR	Exon 1 of 33	ENSP00000355536.5	Q99707-1
MTR	ENST00000961801.1		c.-111C>T	5_prime_UTR	Exon 1 of 31	ENSP00000631860.1
MTR	ENST00000905140.1		c.-111C>T	5_prime_UTR	Exon 1 of 32	ENSP00000575199.1

Frequencies

GnomAD3 genomes

AF:

0.00759

AC:

1156

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00190

AC:

428

AN:

224778

AF XY:

0.00145

show subpopulations

Gnomad AFR exome

AF:

0.0273

Gnomad AMR exome

AF:

0.00118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000131

Gnomad NFE exome

AF:

0.0000887

Gnomad OTH exome

AF:

0.000707

GnomAD4 exome

AF:

0.000774

AC:

1118

AN:

1443666

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

492

AN XY:

718064

show subpopulations

African (AFR)

AF:

0.0263

AC:

872

AN:

33122

American (AMR)

AF:

0.00127

AC:

AN:

43444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

39004

South Asian (SAS)

AF:

0.0000353

AC:

AN:

84964

European-Finnish (FIN)

AF:

0.0000672

AC:

AN:

44636

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000623

AC:

AN:

1107026

Other (OTH)

AF:

0.00175

AC:

105

AN:

59864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

130

194

259

324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00769

AC:

1171

AN:

152362

Hom.:

Cov.:

AF XY:

0.00715

AC XY:

533

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0267

AC:

1112

AN:

41590

American (AMR)

AF:

0.00255

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68038

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00423

Hom.:

Bravo

AF:

0.00882

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Disorders of Intracellular Cobalamin Metabolism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.2

(source)

DANN

Benign

0.91

PhyloP100

0.42

PromoterAI

-0.17

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over