rs2236224

Variant names:

• chr14-64442433-G-A
• rs2236224
• NM_005956.4:c.2136+31G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-64442433-G-A
• chr14-64442433-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.840
• Publications: 31 publications found

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]

MTHFD1 Gene-Disease associations (from GenCC):

• combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000258824 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1321176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.2136+31G>A		intron_variant	Intron 21 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2136+31G>A		intron_variant	Intron 21 of 26		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2136+31G>A		intron_variant	Intron 21 of 27		NM_005956.4	ENSP00000498336.1

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

GnomAD2 exomes AF: 0.396 AC: 98712 AN: 249464 AF XY: 0.397

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 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

African (AFR) AF: 0.123 AC: 4128 AN: 33448

American (AMR) AF: 0.542 AC: 24241 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 10035 AN: 26108

East Asian (EAS) AF: 0.303 AC: 12019 AN: 39678

South Asian (SAS) AF: 0.430 AC: 37047 AN: 86158

European-Finnish (FIN) AF: 0.379 AC: 19707 AN: 52004

Middle Eastern (MID) AF: 0.331 AC: 1903 AN: 5756

European-Non Finnish (NFE) AF: 0.407 AC: 450938 AN: 1109126

Other (OTH) AF: 0.383 AC: 23055 AN: 60266

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

African (AFR) AF: 0.136 AC: 5650 AN: 41494

American (AMR) AF: 0.479 AC: 7315 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1308 AN: 3466

East Asian (EAS) AF: 0.298 AC: 1539 AN: 5156

South Asian (SAS) AF: 0.430 AC: 2072 AN: 4822

European-Finnish (FIN) AF: 0.374 AC: 3951 AN: 10574

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27106 AN: 67968

Other (OTH) AF: 0.342 AC: 723 AN: 2112

Alfa AF: 0.374 Hom.: 8472

Bravo AF: 0.328

Asia WGS AF: 0.350 AC: 1220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0090
DANN	Benign	0.68
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2236224; hg19: chr14-64909151;