Genetic Variant MANSC1:p.Ala355Val (chr12-12330259-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_018050.4(MANSC1):c.1064C>T(p.Ala355Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000854 in 1,614,218 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00067 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 6 hom. )

Consequence

MANSC1
NM_018050.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.124

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009775281).

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANSC1	NM_018050.4 link	c.1064C>T	p.Ala355Val	missense_variant	Exon 4 of 4	ENST00000535902.6	NP_060520.2	Q9H8J5-1
MANSC1	NM_001363613.2 link	c.962C>T	p.Ala321Val	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.1064C>T	p.Ala355Val	missense_variant	Exon 4 of 4	1	NM_018050.4	ENSP00000438205.1	Q9H8J5-1
MANSC1	ENST00000396349.3 link	c.962C>T	p.Ala321Val	missense_variant	Exon 5 of 5	2		ENSP00000379638.3	Q9H8J5-2
MANSC1	ENST00000545735.1 link	c.821C>T	p.Ala274Val	missense_variant	Exon 2 of 2	2		ENSP00000445303.1	F5H3M3

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000632

AC:

159

AN:

251404

Hom.:

AF XY:

0.000780

AC XY:

106

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000862

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000874

AC:

1277

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000891

AC XY:

648

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000979

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152352

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000970

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000881

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1064C>T (p.A355V) 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 1064, causing the alanine (A) at amino acid position 355 to be replaced by a valine (V). 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

0.086

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.7

DANN

Benign

0.96

DEOGEN2

Benign

0.0074

T;.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.044

M_CAP

Benign

0.0099

MetaRNN

Benign

0.0098

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.0080

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.068

T;T;T

Polyphen

0.010

B;.;.

Vest4

0.029

MVP

0.030

MPC

0.12

ClinPred

0.0043

GERP RS

-0.47

Varity_R

0.050

gMVP

0.33

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

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