16-86532217-C-A

Variant names:

• chr16-86532217-C-A
• rs142996375
• NM_001159377.2:c.946G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001159377.2(MTHFSD):​c.946G>T​(p.Asp316Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D316H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MTHFSD NM_001159377.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28061995).

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.946G>T	p.Asp316Tyr	missense	Exon 8 of 8	NP_001152849.1	Q2M296-1
	MTHFSD	NM_001159378.2		c.946G>T	p.Asp316Tyr	missense	Exon 8 of 8	NP_001152850.1	Q2M296-3
	MTHFSD	NM_001159379.2		c.943G>T	p.Asp315Tyr	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.946G>T	p.Asp316Tyr	missense	Exon 8 of 8	ENSP00000354152.6	Q2M296-1
	MTHFSD	ENST00000381214.9	TSL:1	c.946G>T	p.Asp316Tyr	missense	Exon 8 of 8	ENSP00000370612.5	Q2M296-3
	MTHFSD	ENST00000543303.6	TSL:1	c.943G>T	p.Asp315Tyr	missense	Exon 8 of 8	ENSP00000444003.2	Q2M296-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428676 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 708294

African (AFR) AF: 0.00 AC: 0 AN: 32424

American (AMR) AF: 0.00 AC: 0 AN: 40468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24532

East Asian (EAS) AF: 0.00 AC: 0 AN: 38386

South Asian (SAS) AF: 0.00 AC: 0 AN: 81604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095420

Other (OTH) AF: 0.00 AC: 0 AN: 58812

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.013
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.22
Sift	Benign	0.061	T
Sift4G	Benign	0.069	T
Polyphen		0.99	D
Vest4		0.34
MutPred		0.56		Loss of disorder (P = 0.0227)
MVP		0.52
MPC		0.093
ClinPred		0.82	D
GERP RS		3.2
Varity_R		0.13
gMVP		0.55

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: rs142996375; hg19: chr16-86565823;