Variant 6-150865943-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015440.5(MTHFD1L):c.121G>A(p.Gly41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,220,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MTHFD1L
NM_015440.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.91

Variant links:

Genes affected

MTHFD1L (HGNC:21055): (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like) The protein encoded by this gene is involved in the synthesis of tetrahydrofolate (THF) in the mitochondrion. THF is important in the de novo synthesis of purines and thymidylate and in the regeneration of methionine from homocysteine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jun 2011]

MTHFD1L links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07689279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD1L	NM_015440.5 linkuse as main transcript	c.121G>A	p.Gly41Ser	missense_variant	1/28	ENST00000367321.8	NP_056255.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD1L	ENST00000367321.8 linkuse as main transcript	c.121G>A	p.Gly41Ser	missense_variant	1/28	1	NM_015440.5	ENSP00000356290	P4	Q6UB35-1
MTHFD1L	ENST00000367307.8 linkuse as main transcript	c.121G>A	p.Gly41Ser	missense_variant	1/8	1		ENSP00000356276		Q6UB35-2
MTHFD1L	ENST00000611279.4 linkuse as main transcript	c.121G>A	p.Gly41Ser	missense_variant	1/28	5		ENSP00000478253	A1
MTHFD1L	ENST00000367308.8 linkuse as main transcript			upstream_gene_variant		5		ENSP00000356277

Frequencies

GnomAD3 genomes

AF:

0.0000796

AC:

AN:

150662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000264

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:

0.000103

Gnomad OTH

AF:

0.000483

GnomAD4 exome

AF:

0.000151

AC:

162

AN:

1070306

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

508508

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000392

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.0000474

GnomAD4 genome

AF:

0.0000796

AC:

AN:

150662

Hom.:

Cov.:

AF XY:

0.0000544

AC XY:

AN XY:

73586

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000264

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000483

Bravo

AF:

0.0000491

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

Nov 09, 2022

The c.121G>A (p.G41S) alteration is located in exon 1 (coding exon 1) of the MTHFD1L gene. This alteration results from a G to A substitution at nucleotide position 121, causing the glycine (G) at amino acid position 41 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.072

T;.;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.48

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.077

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

N;.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.26

N;.;N

REVEL

Benign

0.041

Sift

Benign

0.11

T;.;D

Sift4G

Benign

0.31

T;T;D

Polyphen

0.056

B;B;B

Vest4

0.32

MutPred

0.23

Gain of phosphorylation at G41 (P = 0.0019);Gain of phosphorylation at G41 (P = 0.0019);Gain of phosphorylation at G41 (P = 0.0019);

MVP

0.061

MPC

0.15

ClinPred

0.14

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.0

Varity_R

0.050

gMVP

0.23

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