12-12330241-T-G

Position:

• chr12-12330241-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000535902.6(MANSC1):​c.1082A>C​(p.Glu361Ala) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E361D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MANSC1 ENST00000535902.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.229

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055625916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANSC1	NM_018050.4	c.1082A>C	p.Glu361Ala	missense_variant	4/4	ENST00000535902.6	NP_060520.2
MANSC1	NM_001363613.2	c.980A>C	p.Glu327Ala	missense_variant	5/5		NP_001350542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANSC1	ENST00000535902.6	c.1082A>C	p.Glu361Ala	missense_variant	4/4	1	NM_018050.4	ENSP00000438205.1
MANSC1	ENST00000396349.3	c.980A>C	p.Glu327Ala	missense_variant	5/5	2		ENSP00000379638.3
MANSC1	ENST00000545735.1	c.839A>C	p.Glu280Ala	missense_variant	2/2	2		ENSP00000445303.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 18, 2022

The c.1082A>C (p.E361A) alteration is located in exon 4 (coding exon 3) of the MANSC1 gene. This alteration results from a A to C substitution at nucleotide position 1082, causing the glutamic acid (E) at amino acid position 361 to be replaced by an alanine (A). 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	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.089	T;.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.084	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.010
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.039	B;.;.
Vest4		0.067
MutPred		0.14		Gain of MoRF binding (P = 0.0597);.;.;
MVP		0.040
MPC		0.10
ClinPred		0.060	T
GERP RS		2.3
Varity_R		0.037
gMVP		0.099

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-12483175;