12-27763223-G-C

Position:

• chr12-27763223-G-C

Variant summary

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

The NM_001146221.5(MANSC4):​c.538C>G​(p.Gln180Glu) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MANSC4 NM_001146221.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.630

Genes affected

MANSC4 (HGNC:40023): (MANSC domain containing 4) 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=0.050418496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANSC4	NM_001146221.5	c.538C>G	p.Gln180Glu	missense_variant	4/4	ENST00000381273.4	NP_001139693.1
MANSC4	XM_011520542.3	c.457C>G	p.Gln153Glu	missense_variant	4/4		XP_011518844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANSC4	ENST00000381273.4	c.538C>G	p.Gln180Glu	missense_variant	4/4	5	NM_001146221.5	ENSP00000370673	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

May 09, 2024

The c.538C>G (p.Q180E) alteration is located in exon 3 (coding exon 3) of the MANSC4 gene. This alteration results from a C to G substitution at nucleotide position 538, causing the glutamine (Q) at amino acid position 180 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	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.025
Sift	Benign	0.091	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.068
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0999);
MVP		0.055
ClinPred		0.043	T
GERP RS		3.3
Varity_R		0.064
gMVP		0.43

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

Other links and lift over

dbSNP: rs2062056094; hg19: chr12-27916156;