chr16-86532025-G-C

Position:

• chr16-86532025-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001159377.2(MTHFSD):​c.1138C>G​(p.Gln380Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MTHFSD NM_001159377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

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]

MTHFSD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20068663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFSD	NM_001159377.2	c.1138C>G	p.Gln380Glu	missense_variant	8/8	ENST00000360900.11	NP_001152849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFSD	ENST00000360900.11	c.1138C>G	p.Gln380Glu	missense_variant	8/8	1	NM_001159377.2	ENSP00000354152.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.1138C>G (p.Q380E) alteration is located in exon 8 (coding exon 8) of the MTHFSD gene. This alteration results from a C to G substitution at nucleotide position 1138, causing the glutamine (Q) at amino acid position 380 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0045	T;T;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.4	M;.;.;.;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;N;.;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.015	D;D;.;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.92	P;.;P;.;.
Vest4		0.23
MutPred		0.28		Loss of MoRF binding (P = 0.0376);.;.;.;Loss of MoRF binding (P = 0.0376);
MVP		0.42
MPC		0.037
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.15
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-86565631;