chr4-71752606-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001204307.1(GC):​c.1364C>G​(p.Thr455Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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. T455K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GC NM_001204307.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>G	p.Thr436Arg	missense	Exon 11 of 13	NP_000574.2
	GC	NM_001204307.1		c.1364C>G	p.Thr455Arg	missense	Exon 12 of 14	NP_001191236.1
	GC	NM_001204306.1		c.1307C>G	p.Thr436Arg	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>G	p.Thr436Arg	missense	Exon 11 of 13	ENSP00000273951.8
	GC	ENST00000504199.5	TSL:1	c.1364C>G	p.Thr455Arg	missense	Exon 12 of 14	ENSP00000421725.1
	GC	ENST00000513476.5	TSL:5	c.1307C>G	p.Thr436Arg	missense	Exon 11 of 12	ENSP00000426683.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461126 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726928

⚠️ 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: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111400

Other (OTH) AF: 0.00 AC: 0 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.11
DANN	Benign	0.89
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.46
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.041
Sift	Benign	0.19	T
Sift4G	Benign	0.41	T
Polyphen		0.90	P
Vest4		0.26
MutPred		0.45		Gain of methylation at T436 (P = 0.02)
MVP		0.14
MPC		0.17
ClinPred		0.34	T
GERP RS		-2.7
Varity_R		0.15
gMVP		0.35
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4588; hg19: chr4-72618323;