chr15-79889156-T-A

Position:

• chr15-79889156-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006441.4(MTHFS):​c.316A>T​(p.Lys106Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFS NM_006441.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.30

Genes affected

MTHFS (HGNC:7437): (methenyltetrahydrofolate synthetase) The protein encoded by this gene is an enzyme that catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, a precursor of reduced folates involved in 1-carbon metabolism. An increased activity of the encoded protein can result in an increased folate turnover rate and folate depletion. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

ST20-MTHFS (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.484 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-79889156-T-A is Pathogenic according to our data. Variant chr15-79889156-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1344538.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFS	NM_006441.4	c.316A>T	p.Lys106Ter	stop_gained	2/3	ENST00000258874.4	NP_006432.1
ST20-MTHFS	NM_001199760.2	c.244A>T	p.Lys82Ter	stop_gained	3/4		NP_001186689.1
MTHFS	NM_001199758.1	c.145A>T	p.Lys49Ter	stop_gained	2/3		NP_001186687.1
MTHFS	NR_037654.2	n.423A>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFS	ENST00000258874.4	c.316A>T	p.Lys106Ter	stop_gained	2/3	1	NM_006441.4	ENSP00000258874	P1
MTHFS	ENST00000559722.2	c.403A>T	p.Lys135Ter	stop_gained	2/3	2		ENSP00000489076
MTHFS	ENST00000560919.5	c.*262A>T		3_prime_UTR_variant, NMD_transcript_variant	2/2	2		ENSP00000454626

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Palindrome, Gene Kavoshgaran Aria

Sep 09, 2021

The stopgain K106X mutation in MTHFS detected in a patient suffers from recurrent seizures, developmental delay and microcephaly. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	A;A
Vest4		0.44
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: chr15-80181498;