6-150866025-C-A

Variant names:

• chr6-150866025-C-A
• rs1053900238
• NM_015440.5:c.203C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015440.5(MTHFD1L):​c.203C>A​(p.Pro68His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,407,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: MTHFD1L NM_015440.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.310

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]

ACMG classification

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=0.12031591).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1L	NM_015440.5	c.203C>A	p.Pro68His	missense_variant	Exon 1 of 28	ENST00000367321.8	NP_056255.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1L	ENST00000367321.8	c.203C>A	p.Pro68His	missense_variant	Exon 1 of 28	1	NM_015440.5	ENSP00000356290.3
MTHFD1L	ENST00000367307.8	c.203C>A	p.Pro68His	missense_variant	Exon 1 of 8	1		ENSP00000356276.4
MTHFD1L	ENST00000611279.4	c.203C>A	p.Pro68His	missense_variant	Exon 1 of 28	5		ENSP00000478253.1
MTHFD1L	ENST00000367308.8	c.80C>A	p.Pro27His	missense_variant	Exon 1 of 11	5		ENSP00000356277.4

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152016 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

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: 0.000478

GnomAD4 exome AF: 0.00000558 AC: 7 AN: 1255068 Hom.: 0 Cov.: 32 AF XY: 0.00000162 AC XY: 1 AN XY: 615980

Gnomad4 AFR exome AF: 0.000199

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: 0.0000389

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152016 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74258

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N;.;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.76	N;.;N
REVEL	Benign	0.032
Sift	Benign	0.049	D;.;D
Sift4G	Benign	0.11	T;T;D
Polyphen		0.68	P;P;D
Vest4		0.17
MutPred		0.29		Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);
MVP		0.10
MPC		0.32
ClinPred		0.42	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.21

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: rs1053900238; hg19: chr6-151187161;