3-112123550-A-T

Position:

• chr3-112123550-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_152785.5(GCSAM):​c.442T>A​(p.Tyr148Asn) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCSAM NM_152785.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

Genes affected

GCSAM (HGNC:20253): (germinal center associated signaling and motility) This gene encodes a protein which may function in signal transduction pathways and whose expression is elevated in germinal cell lymphomas. It contains a putative PDZ-interacting domain, an immunoreceptor tyrosine-based activation motif (ITAM), and two putative SH2 binding sites. In B cells, its expression is specifically induced by interleukin-4. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

C3orf52 (HGNC:):

C3orf52 (HGNC:26255): (chromosome 3 open reading frame 52) Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a mutagenesis_site Prevents IL6 induced phosphorylation. Does not affect the interaction with SYK. (size 0) in uniprot entity GCSAM_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCSAM	NM_152785.5	c.442T>A	p.Tyr148Asn	missense_variant	6/6	ENST00000308910.9	NP_689998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCSAM	ENST00000308910.9	c.442T>A	p.Tyr148Asn	missense_variant	6/6	1	NM_152785.5	ENSP00000309487.4

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

Feb 12, 2024

The c.448T>A (p.Y150N) alteration is located in exon 6 (coding exon 6) of the GCSAM gene. This alteration results from a T to A substitution at nucleotide position 448, causing the tyrosine (Y) at amino acid position 150 to be replaced by an asparagine (N). 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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.9	D;D;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.85
MutPred		0.28		Loss of phosphorylation at Y148 (P = 0.0042);.;.;
MVP		0.27
MPC		0.77
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.73
gMVP		0.41

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: chr3-111842397;