chr6-150905715-A-G

Position:

• chr6-150905715-A-G

Variant summary

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

The NM_015440.5(MTHFD1L):​c.846A>G​(p.Ile282Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFD1L NM_015440.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.253

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1L	NM_015440.5	c.846A>G	p.Ile282Met	missense_variant	8/28	ENST00000367321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1L	ENST00000367321.8	c.846A>G	p.Ile282Met	missense_variant	8/28	1	NM_015440.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Aug 17, 2021

The c.849A>G (p.I283M) alteration is located in exon 8 (coding exon 8) of the MTHFD1L gene. This alteration results from a A to G substitution at nucleotide position 849, causing the isoleucine (I) at amino acid position 283 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	0.090
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	0.86	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;.;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.019	D;.;.
Sift4G	Uncertain	0.037	D;D;T
Polyphen		0.17	B;B;.
Vest4		0.77
MutPred		0.60		Gain of disorder (P = 0.1202);.;.;
MVP		0.55
MPC		0.27
ClinPred		0.87	D
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-151226851;