Genetic Variant NM_018050.4:c.1118C>T (chr12-12330205-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018050.4(MANSC1):c.1118C>T(p.Pro373Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MANSC1
NM_018050.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.532

Variant links:

Genes affected

MANSC1 (HGNC:25505): (MANSC domain containing 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MANSC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.14942461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANSC1	NM_018050.4 link	c.1118C>T	p.Pro373Leu	missense_variant	Exon 4 of 4	ENST00000535902.6	NP_060520.2	Q9H8J5-1
MANSC1	NM_001363613.2 link	c.1016C>T	p.Pro339Leu	missense_variant	Exon 5 of 5		NP_001350542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MANSC1	ENST00000535902.6 link	c.1118C>T	p.Pro373Leu	missense_variant	Exon 4 of 4	1	NM_018050.4	ENSP00000438205.1	Q9H8J5-1
MANSC1	ENST00000396349.3 link	c.1016C>T	p.Pro339Leu	missense_variant	Exon 5 of 5	2		ENSP00000379638.3	Q9H8J5-2
MANSC1	ENST00000545735.1 link	c.875C>T	p.Pro292Leu	missense_variant	Exon 2 of 2	2		ENSP00000445303.1	F5H3M3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251438

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1118C>T (p.P373L) alteration is located in exon 4 (coding exon 3) of the MANSC1 gene. This alteration results from a C to T substitution at nucleotide position 1118, causing the proline (P) at amino acid position 373 to be replaced by a leucine (L). 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

0.075

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;T

Eigen

Benign

-0.015

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.093

M_CAP

Benign

0.025

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.96

D;.;.

Vest4

0.048

MutPred

0.48

Loss of glycosylation at P373 (P = 0.0249);.;.;

MVP

0.14

MPC

0.097

ClinPred

0.48

GERP RS

5.0

Varity_R

0.10

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over