4-74199936-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001144978.3(MTHFD2L):c.594A>G(p.Ile198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTHFD2L NM_001144978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD2L	NM_001144978.3	c.594A>G	p.Ile198Met	missense_variant	4/8	ENST00000325278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD2L	ENST00000325278.7	c.594A>G	p.Ile198Met	missense_variant	4/8	5	NM_001144978.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

The c.594A>G (p.I198M) alteration is located in exon 4 (coding exon 4) of the MTHFD2L gene. This alteration results from a A to G substitution at nucleotide position 594, causing the isoleucine (I) at amino acid position 198 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	0.91	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.025	D;T;D;D
Sift4G	Benign	0.085	T;T;T;T
Polyphen		0.94	.;P;.;.
Vest4		0.56
MutPred		0.68		.;Gain of catalytic residue at I198 (P = 0.0054);.;.;
MVP		0.36
MPC		0.25
ClinPred		0.90	D
GERP RS		-4.1
Varity_R		0.24
gMVP		0.70

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

Other links and lift over

dbSNP: rs1039052766; hg19: chr4-75065653;