rs2236224

chr14-64442433-G-Achr14-64442433-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005956.4(MTHFD1):c.2136+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,609,322 control chromosomes in the GnomAD database, including 128,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (9569 hom., cov: 32)
  • Exomes 𝑓: 0.40 (119311 hom.)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.840

Genes affected

MTHFD1 (HGNC:7432): (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-64442433-G-A is Benign according to our data. Variant chr14-64442433-G-A is described in ClinVar as [Benign]. Clinvar id is 1321176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.2136+31G>A		intron_variant		ENST00000652337.1
MTHFD1	NM_001364837.1	c.2136+31G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2136+31G>A		intron_variant			NM_005956.4	P1
	ENST00000556640.1	n.505+5620C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50187 AN: 151964 Hom.: 9563 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.340

GnomAD3 exomes AF: 0.396 AC: 98712 AN: 249464 Hom.: 20646 AF XY: 0.397 AC XY: 53649 AN XY: 135032

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.384

Gnomad EAS exome AF: 0.296

Gnomad SAS exome AF: 0.433

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.397

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.400 AC: 583073 AN: 1457240 Hom.: 119311 Cov.: 33 AF XY: 0.401 AC XY: 290823 AN XY: 725164

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.384

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.430

Gnomad4 FIN exome AF: 0.379

Gnomad4 NFE exome AF: 0.407

Gnomad4 OTH exome AF: 0.383

GnomAD4 genome AF: 0.330 AC: 50212 AN: 152082 Hom.: 9569 Cov.: 32 AF XY: 0.333 AC XY: 24729 AN XY: 74334

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.479

Gnomad4 ASJ AF: 0.377

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.374

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.342

Alfa AF: 0.369 Hom.: 4659

Bravo AF: 0.328

Asia WGS AF: 0.350 AC: 1220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.0090
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2236224; hg19: chr14-64909151;