3-112125234-G-A

Variant names:

• chr3-112125234-G-A
• rs147855189
• NM_152785.5:c.211C>T

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.211C>T​(p.Pro71Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,424,168 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. 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. P71T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GCSAM NM_152785.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• 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=0.075579196).

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.211C>T	p.Pro71Ser	missense	Exon 5 of 6	NP_689998.1	Q8N6F7-1
	GCSAM	NM_001190259.2		c.217C>T	p.Pro73Ser	missense	Exon 5 of 6	NP_001177188.1	Q8N6F7-2
	GCSAM	NM_001190260.2		c.166C>T	p.Pro56Ser	missense	Exon 4 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.211C>T	p.Pro71Ser	missense	Exon 5 of 6	ENSP00000309487.4	Q8N6F7-1
	C3orf52	ENST00000467942.2	TSL:1	n.951-2999G>A		intron	N/A
	GCSAM	ENST00000484193.5	TSL:2	c.217C>T	p.Pro73Ser	missense	Exon 5 of 6	ENSP00000419485.1	Q8N6F7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251084 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1424168 Hom.: 0 Cov.: 25 AF XY: 0.00000281 AC XY: 2 AN XY: 711092

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32604

American (AMR) AF: 0.0000448 AC: 2 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 85478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077840

Other (OTH) AF: 0.00 AC: 0 AN: 59100

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00846340), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.65
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.4
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.034
Sift	Benign	0.16	T
Sift4G	Benign	0.14	T
Polyphen		0.45	B
Vest4		0.46
MutPred		0.20		Gain of phosphorylation at P71 (P = 0.0571)
MVP		0.055
MPC		0.15
ClinPred		0.26	T
GERP RS		2.4
Varity_R		0.089
gMVP		0.046
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs147855189; hg19: chr3-111844081;