Variant chr4-71754414-T-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000583.4(GC):c.1259A>T(p.Lys420Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000155 in 1,292,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

GC
NM_000583.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83

Variant links:

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]

GC links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GC	NM_000583.4 linkuse as main transcript	c.1259A>T	p.Lys420Ile	missense_variant	10/13	ENST00000273951.13
GC	NM_001204307.1 linkuse as main transcript	c.1316A>T	p.Lys439Ile	missense_variant	11/14
GC	NM_001204306.1 linkuse as main transcript	c.1259A>T	p.Lys420Ile	missense_variant	11/14
GC	XM_006714177.3 linkuse as main transcript	c.1259A>T	p.Lys420Ile	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GC	ENST00000273951.13 linkuse as main transcript	c.1259A>T	p.Lys420Ile	missense_variant	10/13	1	NM_000583.4	P1	P02774-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000849

AC:

AN:

235700

Hom.:

AF XY:

0.00000784

AC XY:

AN XY:

127534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000634

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000155

AC:

AN:

1292838

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

651282

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000483

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.1259A>T (p.K420I) alteration is located in exon 10 (coding exon 10) of the GC gene. This alteration results from a A to T substitution at nucleotide position 1259, causing the lysine (K) at amino acid position 420 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.9

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0030

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.54

MutPred

0.64

Loss of disorder (P = 0.0018);.;Loss of disorder (P = 0.0018);

MVP

0.17

MPC

0.43

ClinPred

0.95

GERP RS

5.5

Varity_R

0.62

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over