14-64449480-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005956.4(MTHFD1):c.2315G>A(p.Arg772His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,902 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R772C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0069 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (14 hom.)
• Consequence: MTHFD1 NM_005956.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.929

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]

ZBTB25 (HGNC:13112): (zinc finger and BTB domain containing 25) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037965775).
• BP6: Variant 14-64449480-G-A is Benign according to our data. Variant chr14-64449480-G-A is described in ClinVar as [Benign]. Clinvar id is 781286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64449480-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00694 (1056/152270) while in subpopulation AFR AF= 0.024 (999/41542). AF 95% confidence interval is 0.0228. There are 8 homozygotes in gnomad4. There are 494 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.2315G>A	p.Arg772His	missense_variant	24/28	ENST00000652337.1
MTHFD1	NM_001364837.1	c.2315G>A	p.Arg772His	missense_variant	24/27
ZBTB25	NM_001304508.1	c.*71C>T		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2315G>A	p.Arg772His	missense_variant	24/28		NM_005956.4	P1

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1054 AN: 152152 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00184 AC: 461 AN: 251224 Hom.: 4 AF XY: 0.00137 AC XY: 186 AN XY: 135772

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000672 AC: 982 AN: 1461632 Hom.: 14 Cov.: 31 AF XY: 0.000576 AC XY: 419 AN XY: 727124

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00694 AC: 1056 AN: 152270 Hom.: 8 Cov.: 32 AF XY: 0.00663 AC XY: 494 AN XY: 74464

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.000821 Hom.: 2

Bravo AF: 0.00792

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MTHFD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	8.8
Dann	Uncertain	0.99
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.033
Sift	Uncertain	0.017	D;.
Sift4G	Uncertain	0.039	D;D
Polyphen		0.036	B;.
Vest4		0.14
MVP		0.28
MPC		0.45
ClinPred		0.012	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs149899012; hg19: chr14-64916198;