rs4588

chr4-71752606-G-Achr4-71752606-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000583.4(GC):c.1307C>T(p.Thr436Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. T436K) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: GC NM_000583.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0885407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GC	NM_000583.4	c.1307C>T	p.Thr436Met	missense_variant	11/13	ENST00000273951.13
GC	NM_001204307.1	c.1364C>T	p.Thr455Met	missense_variant	12/14
GC	NM_001204306.1	c.1307C>T	p.Thr436Met	missense_variant	12/14
GC	XM_006714177.3	c.1262+1805C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GC	ENST00000273951.13	c.1307C>T	p.Thr436Met	missense_variant	11/13	1	NM_000583.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251214 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS 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: 0.00000616 AC: 9 AN: 1461126 Hom.: 1 Cov.: 36 AF XY: 0.00000550 AC XY: 4 AN XY: 726928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.1
DANN	Benign	0.93
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.35	T;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.017
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.31	.;.;B
Vest4		0.18
MutPred		0.43		Gain of stability (P = 0.0212);.;Gain of stability (P = 0.0212);
MVP		0.085
MPC		0.063
ClinPred		0.057	T
GERP RS		-2.7
Varity_R		0.053
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs4588; hg19: chr4-72618323;