Variant 4-74174687-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001144978.3(MTHFD2L):c.325G>A(p.Val109Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,492,194 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 1 hom. )

Consequence

MTHFD2L
NM_001144978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.85

Variant links:

Genes affected

MTHFD2L (HGNC:31865): (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 like) Predicted to enable methenyltetrahydrofolate cyclohydrolase activity; methylenetetrahydrofolate dehydrogenase (NAD+) activity; and methylenetetrahydrofolate dehydrogenase (NADP+) activity. Predicted to be involved in tetrahydrofolate interconversion. Predicted to be located in mitochondrial matrix. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

MTHFD2L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049565822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD2L	NM_001144978.3 linkuse as main transcript	c.325G>A	p.Val109Ile	missense_variant	2/8	ENST00000325278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD2L	ENST00000325278.7 linkuse as main transcript	c.325G>A	p.Val109Ile	missense_variant	2/8	5	NM_001144978.3	P1	Q9H903-4

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000823

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000627

AC:

112

AN:

178656

Hom.:

AF XY:

0.000611

AC XY:

AN XY:

98156

show subpopulations

Gnomad AFR exome

AF:

0.0000826

Gnomad AMR exome

AF:

0.000235

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000526

Gnomad FIN exome

AF:

0.000103

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000273

GnomAD4 exome

AF:

0.000881

AC:

1180

AN:

1339970

Hom.:

Cov.:

AF XY:

0.000849

AC XY:

560

AN XY:

659698

show subpopulations

Gnomad4 AFR exome

AF:

0.0000716

Gnomad4 AMR exome

AF:

0.000292

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000452

Gnomad4 FIN exome

AF:

0.0000398

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.000914

GnomAD4 genome

AF:

0.000414

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000823

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000931

Hom.:

Bravo

AF:

0.000536

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000552

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.325G>A (p.V109I) alteration is located in exon 2 (coding exon 2) of the MTHFD2L gene. This alteration results from a G to A substitution at nucleotide position 325, causing the valine (V) at amino acid position 109 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.49

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;.

Eigen

Benign

-0.00043

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.0094

MetaRNN

Benign

0.050

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.;.

MutationTaster

Benign

0.98

D;D;D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.52

N;N;N

REVEL

Benign

0.024

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.39

B;.;.

Vest4

0.24

MVP

0.39

MPC

0.078

ClinPred

0.033

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over