chr16-86532418-C-A

Variant names:

• chr16-86532418-C-A
• rs776250628
• NM_001159377.2:c.745G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001159377.2(MTHFSD):​c.745G>T​(p.Ala249Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,495,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MTHFSD NM_001159377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15
• Publications: 1 publications found

Genes affected

MTHFSD (HGNC:25778): (methenyltetrahydrofolate synthetase domain containing) Enables RNA binding activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18069011).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159377.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFSD	NM_001159377.2	MANE Select	c.745G>T	p.Ala249Ser	missense	Exon 8 of 8	NP_001152849.1	Q2M296-1
	MTHFSD	NM_001159378.2		c.745G>T	p.Ala249Ser	missense	Exon 8 of 8	NP_001152850.1	Q2M296-3
	MTHFSD	NM_001159379.2		c.742G>T	p.Ala248Ser	missense	Exon 8 of 8	NP_001152851.1	Q2M296-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFSD	ENST00000360900.11	TSL:1 MANE Select	c.745G>T	p.Ala249Ser	missense	Exon 8 of 8	ENSP00000354152.6	Q2M296-1
	MTHFSD	ENST00000381214.9	TSL:1	c.745G>T	p.Ala249Ser	missense	Exon 8 of 8	ENSP00000370612.5	Q2M296-3
	MTHFSD	ENST00000543303.6	TSL:1	c.742G>T	p.Ala248Ser	missense	Exon 8 of 8	ENSP00000444003.2	Q2M296-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 5 AN: 114338 AF XY: 0.0000331

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000690

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000781

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 17 AN: 1343786 Hom.: 0 Cov.: 34 AF XY: 0.0000106 AC XY: 7 AN XY: 658076

African (AFR) AF: 0.00 AC: 0 AN: 29322

American (AMR) AF: 0.0000770 AC: 2 AN: 25978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20742

East Asian (EAS) AF: 0.00 AC: 0 AN: 35134

South Asian (SAS) AF: 0.00 AC: 0 AN: 69068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5354

European-Non Finnish (NFE) AF: 0.0000142 AC: 15 AN: 1054666

Other (OTH) AF: 0.00 AC: 0 AN: 55408

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0027	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Benign	0.23	T
Polyphen		0.98	D
Vest4		0.32
MutPred		0.33		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.33
MPC		0.087
ClinPred		0.56	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.35
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs776250628; hg19: chr16-86566024;