rs7041

Positions:

• chr4-71752617-A-C
• chr4-71752617-A-G
• chr4-71752617-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000583.4(GC):​c.1296T>G​(p.Asp432Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,611,978 control chromosomes in the GnomAD database, including 240,297 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (17944 hom., cov: 32)
  • Exomes 𝑓: 0.55 (222353 hom.)
• Consequence: GC NM_000583.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -3.89

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.460173E-6).
• BP6: Variant 4-71752617-A-C is Benign according to our data. Variant chr4-71752617-A-C is described in ClinVar as [Benign]. Clinvar id is 15987.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GC	NM_000583.4	c.1296T>G	p.Asp432Glu	missense_variant	11/13	ENST00000273951.13	NP_000574.2
GC	NM_001204307.1	c.1353T>G	p.Asp451Glu	missense_variant	12/14		NP_001191236.1
GC	NM_001204306.1	c.1296T>G	p.Asp432Glu	missense_variant	12/14		NP_001191235.1
GC	XM_006714177.3	c.1262+1794T>G		intron_variant			XP_006714240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GC	ENST00000273951.13	c.1296T>G	p.Asp432Glu	missense_variant	11/13	1	NM_000583.4	ENSP00000273951	P1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68273 AN: 151994 Hom.: 17953 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.469

GnomAD3 exomes AF: 0.522 AC: 131047 AN: 251206 Hom.: 36331 AF XY: 0.531 AC XY: 72119 AN XY: 135784

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.508

Gnomad ASJ exome AF: 0.598

Gnomad EAS exome AF: 0.286

Gnomad SAS exome AF: 0.551

Gnomad FIN exome AF: 0.675

Gnomad NFE exome AF: 0.571

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.545 AC: 796152 AN: 1459866 Hom.: 222353 Cov.: 34 AF XY: 0.547 AC XY: 397490 AN XY: 726388

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.599

Gnomad4 EAS exome AF: 0.269

Gnomad4 SAS exome AF: 0.549

Gnomad4 FIN exome AF: 0.669

Gnomad4 NFE exome AF: 0.562

Gnomad4 OTH exome AF: 0.529

GnomAD4 genome AF: 0.449 AC: 68278 AN: 152112 Hom.: 17944 Cov.: 32 AF XY: 0.459 AC XY: 34100 AN XY: 74350

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.518

Gnomad4 ASJ AF: 0.596

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.550

Gnomad4 FIN AF: 0.689

Gnomad4 NFE AF: 0.565

Gnomad4 OTH AF: 0.467

Alfa AF: 0.538 Hom.: 52790

Bravo AF: 0.420

TwinsUK AF: 0.559 AC: 2073

ALSPAC AF: 0.555 AC: 2140

ESP6500AA AF: 0.174 AC: 765

ESP6500EA AF: 0.559 AC: 4808

ExAC AF: 0.516 AC: 62622

Asia WGS AF: 0.413 AC: 1434 AN: 3478

EpiCase AF: 0.556

EpiControl AF: 0.566

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

GC1/GC2 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jun 01, 1992

- -

Periodontitis Benign:1

Benign, no assertion criteria provided

case-control

Genetics Laboratory, Lanzhou University

Apr 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0010
DANN	Benign	0.46
DEOGEN2	Benign	0.073	T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.42	T;T;T
MetaRNN	Benign	0.0000045	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.76	N;N;N
REVEL	Benign	0.037
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.040
MutPred		0.39		Gain of glycosylation at T434 (P = 0.0279);.;Gain of glycosylation at T434 (P = 0.0279);
MPC		0.048
ClinPred		0.039	T
GERP RS		-10
Varity_R		0.17
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs7041; hg19: chr4-72618334; COSMIC: COSV56735134;