chr14-64449470-C-T

Position:

• chr14-64449470-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005956.4(MTHFD1):​c.2305C>T​(p.Leu769Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,613,774 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. L769L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (192 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (210 hom.)
• Consequence: MTHFD1 NM_005956.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.04

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=0.002995789).
• BP6: Variant 14-64449470-C-T is Benign according to our data. Variant chr14-64449470-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 779686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.097 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.2305C>T	p.Leu769Phe	missense_variant	24/28	ENST00000652337.1
MTHFD1	NM_001364837.1	c.2305C>T	p.Leu769Phe	missense_variant	24/27
ZBTB25	NM_001304508.1	c.*81G>A		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2305C>T	p.Leu769Phe	missense_variant	24/28		NM_005956.4	P1

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4337 AN: 152168 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.00761 AC: 1911 AN: 251250 Hom.: 91 AF XY: 0.00535 AC XY: 726 AN XY: 135796

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00310 AC: 4533 AN: 1461488 Hom.: 210 Cov.: 31 AF XY: 0.00266 AC XY: 1933 AN XY: 727048

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.00572

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.00760

GnomAD4 genome AF: 0.0285 AC: 4342 AN: 152286 Hom.: 192 Cov.: 32 AF XY: 0.0274 AC XY: 2040 AN XY: 74468

Gnomad4 AFR AF: 0.0996

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.00516 Hom.: 57

Bravo AF: 0.0326

ESP6500AA AF: 0.0990 AC: 436

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00925 AC: 1123

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 30924900) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.056
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;D
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.079
Sift	Uncertain	0.0090	D;.
Sift4G	Benign	0.099	T;T
Polyphen		0.077	B;.
Vest4		0.64
MVP		0.34
MPC		1.1
ClinPred		0.043	T
GERP RS		4.3

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: rs17857382; hg19: chr14-64916188;