4-71752606-G-T

Variant names:

• chr4-71752606-G-T
• rs4588
• NM_000583.4:c.1307C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001204307.1(GC):​c.1364C>A​(p.Thr455Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,612,616 control chromosomes in the GnomAD database, including 62,145 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 0.22 (4369 hom., cov: 32)
  • Exomes 𝑓: 0.28 (57776 hom.)
• Consequence: GC NM_001204307.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: -0.459
• Publications: 610 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004927546).
• BP6: Variant 4-71752606-G-T is Benign according to our data. Variant chr4-71752606-G-T is described in ClinVar as Benign. ClinVar VariationId is 15986.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204307.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GC	NM_000583.4	MANE Select	c.1307C>A	p.Thr436Lys	missense	Exon 11 of 13	NP_000574.2
	GC	NM_001204307.1		c.1364C>A	p.Thr455Lys	missense	Exon 12 of 14	NP_001191236.1
	GC	NM_001204306.1		c.1307C>A	p.Thr436Lys	missense	Exon 12 of 14	NP_001191235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GC	ENST00000273951.13	TSL:1 MANE Select	c.1307C>A	p.Thr436Lys	missense	Exon 11 of 13	ENSP00000273951.8
	GC	ENST00000504199.5	TSL:1	c.1364C>A	p.Thr455Lys	missense	Exon 12 of 14	ENSP00000421725.1
	GC	ENST00000513476.5	TSL:5	c.1307C>A	p.Thr436Lys	missense	Exon 11 of 12	ENSP00000426683.1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33938 AN: 152010 Hom.: 4364 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.253 AC: 63579 AN: 251214 AF XY: 0.260

Gnomad AFR exome AF: 0.0981

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.285

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.278 AC: 406250 AN: 1460488 Hom.: 57776 Cov.: 36 AF XY: 0.279 AC XY: 203015 AN XY: 726636

African (AFR) AF: 0.0963 AC: 3220 AN: 33448

American (AMR) AF: 0.211 AC: 9425 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7519 AN: 26124

East Asian (EAS) AF: 0.268 AC: 10646 AN: 39674

South Asian (SAS) AF: 0.298 AC: 25659 AN: 86186

European-Finnish (FIN) AF: 0.203 AC: 10832 AN: 53416

Middle Eastern (MID) AF: 0.210 AC: 1212 AN: 5758

European-Non Finnish (NFE) AF: 0.290 AC: 321921 AN: 1110870

Other (OTH) AF: 0.262 AC: 15816 AN: 60346

GnomAD4 genome AF: 0.223 AC: 33964 AN: 152128 Hom.: 4369 Cov.: 32 AF XY: 0.219 AC XY: 16279 AN XY: 74366

African (AFR) AF: 0.103 AC: 4289 AN: 41528

American (AMR) AF: 0.222 AC: 3394 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3468

East Asian (EAS) AF: 0.256 AC: 1320 AN: 5152

South Asian (SAS) AF: 0.288 AC: 1387 AN: 4820

European-Finnish (FIN) AF: 0.197 AC: 2088 AN: 10584

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19557 AN: 67986

Other (OTH) AF: 0.239 AC: 504 AN: 2110

Alfa AF: 0.263 Hom.: 17637

Bravo AF: 0.219

TwinsUK AF: 0.292 AC: 1082

ALSPAC AF: 0.288 AC: 1110

ESP6500AA AF: 0.106 AC: 467

ESP6500EA AF: 0.289 AC: 2489

ExAC AF: 0.253 AC: 30677

Asia WGS AF: 0.232 AC: 811 AN: 3478

EpiCase AF: 0.286

EpiControl AF: 0.282

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	GC1/GC2 POLYMORPHISM (1)
-	-	1	not provided (1)
-	-	-	Levothyroxine response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.078
DANN	Benign	0.19
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.46
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.0070
Sift	Benign	0.48	T
Sift4G	Benign	0.87	T
Polyphen		0.0090	B
Vest4		0.080
MPC		0.060
ClinPred		0.00012	T
GERP RS		-2.7
Varity_R		0.10
gMVP		0.32
Mutation Taster		=97/3	polymorphism (auto)

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: rs4588; hg19: chr4-72618323; COSMIC: COSV56735386;