4-71752617-A-T

Variant names:

• chr4-71752617-A-T
• rs7041
• NM_000583.4:c.1296T>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000583.4(GC):​c.1296T>A​(p.Asp432Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: GC NM_000583.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061386228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GC	NM_000583.4	c.1296T>A	p.Asp432Glu	missense_variant	Exon 11 of 13	ENST00000273951.13	NP_000574.2
GC	NM_001204307.1	c.1353T>A	p.Asp451Glu	missense_variant	Exon 12 of 14		NP_001191236.1
GC	NM_001204306.1	c.1296T>A	p.Asp432Glu	missense_variant	Exon 12 of 14		NP_001191235.1
GC	XM_006714177.3	c.1262+1794T>A		intron_variant	Intron 10 of 11		XP_006714240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GC	ENST00000273951.13	c.1296T>A	p.Asp432Glu	missense_variant	Exon 11 of 13	1	NM_000583.4	ENSP00000273951.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251206 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461078 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 726900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0010
DANN	Benign	0.49
DEOGEN2	Benign	0.073	T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.42	T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.76	N;N;N
REVEL	Benign	0.035
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);
MVP		0.048
MPC		0.048
ClinPred		0.15	T
GERP RS		-10
Varity_R		0.17
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs7041; hg19: chr4-72618334;