4-74174525-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001144978.3(MTHFD2L):c.163T>C(p.Ser55Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MTHFD2L NM_001144978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD2L	NM_001144978.3	c.163T>C	p.Ser55Pro	missense_variant	2/8	ENST00000325278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD2L	ENST00000325278.7	c.163T>C	p.Ser55Pro	missense_variant	2/8	5	NM_001144978.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000952 AC: 2 AN: 210136 Hom.: 0 AF XY: 0.00000874 AC XY: 1 AN XY: 114368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000135

Gnomad SAS 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: 0.00000142 AC: 2 AN: 1407380 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 698710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000539

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Feb 21, 2024

The c.163T>C (p.S55P) alteration is located in exon 2 (coding exon 2) of the MTHFD2L gene. This alteration results from a T to C substitution at nucleotide position 163, causing the serine (S) at amino acid position 55 to be replaced by a proline (P). 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	0.28
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.75		Loss of glycosylation at S55 (P = 0.032);
MVP		0.52
MPC		0.52
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1300774482; hg19: chr4-75040242;