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GeneBe

rs4588

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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. 13/19 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

Scores

17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.459
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance.

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
GCNM_000583.4 linkuse as main transcriptc.1307C>T p.Thr436Met missense_variant 11/13 ENST00000273951.13
GCNM_001204307.1 linkuse as main transcriptc.1364C>T p.Thr455Met missense_variant 12/14
GCNM_001204306.1 linkuse as main transcriptc.1307C>T p.Thr436Met missense_variant 12/14
GCXM_006714177.3 linkuse as main transcriptc.1262+1805C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GCENST00000273951.13 linkuse as main transcriptc.1307C>T p.Thr436Met missense_variant 11/131 NM_000583.4 P1P02774-1

Frequencies

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

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

Other links and lift over

dbSNP: rs4588; hg19: chr4-72618323; API