Genetic Variant MTHFD2L:p.Arg14His (chr4-74158179-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001144978.3(MTHFD2L):c.41G>A(p.Arg14His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,374,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

MTHFD2L
NM_001144978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0760

Publications

0 publications found

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:

ENSG00000269559 (HGNC:):

ENSG00000269559 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0743607).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTHFD2L	NM_001144978.3	MANE Select	c.41G>A	p.Arg14His	missense	Exon 1 of 8	NP_001138450.1	Q9H903-4
MTHFD2L	NM_001351329.2		c.41G>A	p.Arg14His	missense	Exon 1 of 2	NP_001338258.1
MTHFD2L	NM_001351331.2		c.41G>A	p.Arg14His	missense	Exon 1 of 3	NP_001338260.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTHFD2L	ENST00000325278.7	TSL:5 MANE Select	c.41G>A	p.Arg14His	missense	Exon 1 of 8	ENSP00000321984.7	Q9H903-4
MTHFD2L	ENST00000461101.1	TSL:1	n.62G>A		non_coding_transcript_exon	Exon 1 of 2
MTHFD2L	ENST00000429335.5	TSL:1	n.-32+14712G>A		intron	N/A	ENSP00000409391.1	Q8IY64

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

125034

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000906

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000218

AC:

AN:

1374728

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

676750

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30992

American (AMR)

AF:

0.0000603

AC:

AN:

33160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23766

East Asian (EAS)

AF:

0.00

AC:

AN:

35442

South Asian (SAS)

AF:

0.00

AC:

AN:

76090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5256

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1070206

Other (OTH)

AF:

0.00

AC:

AN:

57028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.076

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.29

REVEL

Benign

0.012

Sift

Uncertain

0.026

Sift4G

Benign

0.097

Polyphen

0.0010

Vest4

0.15

MutPred

0.32

Loss of methylation at R14 (P = 0.0083)

MVP

0.085

MPC

0.41

ClinPred

0.27

GERP RS

1.2

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.063

gMVP

0.22

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over