4-71765507-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000583.4(GC):c.398T>A(p.Phe133Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GC NM_000583.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GC	NM_000583.4	c.398T>A	p.Phe133Tyr	missense_variant	4/13	ENST00000273951.13
GC	NM_001204307.1	c.455T>A	p.Phe152Tyr	missense_variant	5/14
GC	NM_001204306.1	c.398T>A	p.Phe133Tyr	missense_variant	5/14
GC	XM_006714177.3	c.398T>A	p.Phe133Tyr	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GC	ENST00000273951.13	c.398T>A	p.Phe133Tyr	missense_variant	4/13	1	NM_000583.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.398T>A (p.F133Y) alteration is located in exon 4 (coding exon 4) of the GC gene. This alteration results from a T to A substitution at nucleotide position 398, causing the phenylalanine (F) at amino acid position 133 to be replaced by a tyrosine (Y). 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	Benign	0.23
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.020	D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.48
MutPred		0.67		Gain of glycosylation at Y136 (P = 0.0076);.;Gain of glycosylation at Y136 (P = 0.0076);Gain of glycosylation at Y136 (P = 0.0076);
MVP		0.57
MPC		0.33
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-72631224;