rs3733359

chr4-71784057-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000504199.5(GC):c.22-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 1,586,812 control chromosomes in the GnomAD database, including 9,246 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1866 hom., cov: 32)
  • Exomes 𝑓: 0.079 (7380 hom.)
• Consequence: GC ENST00000504199.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003753
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43

Genes affected

GC (HGNC:4187): (GC vitamin D binding protein) The protein encoded by this gene belongs to the albumin gene family. It is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types. It binds to vitamin D and its plasma metabolites and transports them to target tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GC	NM_000583.4	c.-39C>T		5_prime_UTR_variant	1/13	ENST00000273951.13
GC	XM_006714177.3	c.-39C>T		5_prime_UTR_variant	1/12
GC	NM_001204306.1	c.-36-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
GC	NM_001204307.1	c.22-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GC	ENST00000273951.13	c.-39C>T		5_prime_UTR_variant	1/13	1	NM_000583.4	P1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19384 AN: 151372 Hom.: 1859 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0955

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.0597

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.122 AC: 28747 AN: 236118 Hom.: 2902 AF XY: 0.114 AC XY: 14621 AN XY: 127720

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.0936

Gnomad EAS exome AF: 0.390

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0610

Gnomad OTH exome AF: 0.0980

GnomAD4 exome AF: 0.0791 AC: 113497 AN: 1435320 Hom.: 7380 Cov.: 27 AF XY: 0.0796 AC XY: 56804 AN XY: 713592

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.173

Gnomad4 ASJ exome AF: 0.0908

Gnomad4 EAS exome AF: 0.348

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0578

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.128 AC: 19420 AN: 151492 Hom.: 1866 Cov.: 32 AF XY: 0.126 AC XY: 9352 AN XY: 74016

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0955

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.0597

Gnomad4 OTH AF: 0.124

Alfa AF: 0.0774 Hom.: 1416

Bravo AF: 0.144

Asia WGS AF: 0.251 AC: 872 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	9.5
Dann	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.0020
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: rs3733359; hg19: chr4-72649774; COSMIC: COSV56738424; COSMIC: COSV56738424;