3-112123586-T-C

Variant names:

• chr3-112123586-T-C
• rs1016658279
• NM_152785.5:c.406A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152785.5(GCSAM):​c.406A>G​(p.Thr136Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Synonymous variant affecting the same amino acid position (i.e. T136T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: GCSAM NM_152785.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.348
• Publications: 1 publications found

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: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]

C3orf52 Gene-Disease associations (from GenCC):

• hypotrichosis 15

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09020877).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152785.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSAM	NM_152785.5	MANE Select	c.406A>G	p.Thr136Ala	missense	Exon 6 of 6	NP_689998.1	Q8N6F7-1
	GCSAM	NM_001190259.2		c.412A>G	p.Thr138Ala	missense	Exon 6 of 6	NP_001177188.1	Q8N6F7-2
	GCSAM	NM_001190260.2		c.361A>G	p.Thr121Ala	missense	Exon 5 of 5	NP_001177189.1	Q8N6F7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSAM	ENST00000308910.9	TSL:1 MANE Select	c.406A>G	p.Thr136Ala	missense	Exon 6 of 6	ENSP00000309487.4	Q8N6F7-1
	C3orf52	ENST00000467942.2	TSL:1	n.950+4024T>C		intron	N/A
	GCSAM	ENST00000484193.5	TSL:2	c.412A>G	p.Thr138Ala	missense	Exon 6 of 6	ENSP00000419485.1	Q8N6F7-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.1
DANN	Benign	0.94
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.042	N
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.35
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.080
Sift	Uncertain	0.016	D
Sift4G	Benign	0.10	T
Polyphen		0.88	P
Vest4		0.030
MutPred		0.088		Loss of phosphorylation at T136 (P = 0.0053)
MVP		0.12
MPC		0.27
ClinPred		0.20	T
GERP RS		-1.9
Varity_R		0.055
gMVP		0.097
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1016658279; hg19: chr3-111842433; COSMIC: COSV58263159; COSMIC: COSV58263159;