3-112123498-C-G

Variant names:

• chr3-112123498-C-G
• rs371130266
• NM_152785.5:c.494G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152785.5(GCSAM):​c.494G>C​(p.Arg165Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GCSAM NM_152785.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.33
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06743547).

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.494G>C	p.Arg165Pro	missense	Exon 6 of 6	NP_689998.1	Q8N6F7-1
	GCSAM	NM_001190259.2		c.500G>C	p.Arg167Pro	missense	Exon 6 of 6	NP_001177188.1	Q8N6F7-2
	GCSAM	NM_001190260.2		c.449G>C	p.Arg150Pro	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.494G>C	p.Arg165Pro	missense	Exon 6 of 6	ENSP00000309487.4	Q8N6F7-1
	C3orf52	ENST00000467942.2	TSL:1	n.950+3936C>G		intron	N/A
	GCSAM	ENST00000484193.5	TSL:2	c.500G>C	p.Arg167Pro	missense	Exon 6 of 6	ENSP00000419485.1	Q8N6F7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.0030
DANN	Benign	0.65
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.033	N
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		-3.3
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.13	T
Sift4G	Uncertain	0.060	T
Polyphen		0.47	P
Vest4		0.25
MutPred		0.18		Gain of glycosylation at R165 (P = 0.0061)
MVP		0.048
MPC		0.32
ClinPred		0.19	T
GERP RS		-7.2
Varity_R		0.11
gMVP		0.10
Mutation Taster		=99/1	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: rs371130266; hg19: chr3-111842345;