Genetic Variant MTHFSD:p.Arg366Leu (chr16-86532066-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001159377.2(MTHFSD):c.1097G>T(p.Arg366Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,521,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MTHFSD
NM_001159377.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.670

Publications

3 publications found

Variant links:

Genes affected

MTHFSD (HGNC:25778): (methenyltetrahydrofolate synthetase domain containing) Enables RNA binding activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MTHFSD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09620175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFSD	NM_001159377.2 link	c.1097G>T	p.Arg366Leu	missense_variant	Exon 8 of 8	ENST00000360900.11	NP_001152849.1	Q2M296-1B4DN17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFSD	ENST00000360900.11 link	c.1097G>T	p.Arg366Leu	missense_variant	Exon 8 of 8	1	NM_001159377.2	ENSP00000354152.6		Q2M296-1

Frequencies

GnomAD3 genomes

AF:

0.000185

AC:

AN:

151696

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000298

AC:

AN:

167510

AF XY:

0.0000324

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

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:

0.0000183

AC:

AN:

1369768

Hom.:

Cov.:

AF XY:

0.0000119

AC XY:

AN XY:

671830

show subpopulations

African (AFR)

AF:

0.000784

AC:

AN:

30618

American (AMR)

AF:

0.00

AC:

AN:

33632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21692

East Asian (EAS)

AF:

0.00

AC:

AN:

37430

South Asian (SAS)

AF:

0.00

AC:

AN:

74626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4626

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1067856

Other (OTH)

AF:

0.0000177

AC:

AN:

56362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000184

AC:

AN:

151814

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.000651

AC:

AN:

41458

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5048

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67894

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000219

ESP6500AA

AF:

0.000561

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000510

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1097G>T (p.R366L) alteration is located in exon 8 (coding exon 8) of the MTHFSD gene. This alteration results from a G to T substitution at nucleotide position 1097, causing the arginine (R) at amino acid position 366 to be replaced by a leucine (L). 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

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0013

T;T;.;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Benign

0.0080

MetaRNN

Benign

0.096

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.;.;.;L

PhyloP100

-0.67

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

N;N;.;N;N

REVEL

Benign

0.052

Sift

Benign

0.10

T;T;.;T;T

Sift4G

Benign

0.38

T;T;T;T;T

Polyphen

0.60

P;.;P;.;.

Vest4

0.27

MVP

0.18

MPC

0.030

ClinPred

0.061

GERP RS

-3.9

Varity_R

0.18

gMVP

0.34

Mutation Taster

=91/9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over