4-71752545-G-T

Position:

• chr4-71752545-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_000583.4(GC):​c.1368C>A​(p.Asn456Lys) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N456Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GC NM_000583.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0600

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-71752547-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 3242552.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 4-71752545-G-T is Pathogenic according to our data. Variant chr4-71752545-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3336641.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GC	NM_000583.4	c.1368C>A	p.Asn456Lys	missense_variant	11/13	ENST00000273951.13
GC	NM_001204307.1	c.1425C>A	p.Asn475Lys	missense_variant	12/14
GC	NM_001204306.1	c.1368C>A	p.Asn456Lys	missense_variant	12/14
GC	XM_006714177.3	c.1262+1866C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GC	ENST00000273951.13	c.1368C>A	p.Asn456Lys	missense_variant	11/13	1	NM_000583.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Chronic obstructive pulmonary disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Dr Mariam's Lab, University of the Punjab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;T
Eigen	Benign	0.025
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.9	M;.;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.015	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.56
MutPred		0.77		Gain of ubiquitination at N456 (P = 0.0131);.;Gain of ubiquitination at N456 (P = 0.0131);
MVP		0.25
MPC		0.36
ClinPred		0.97	D
GERP RS		0.62
Varity_R		0.43
gMVP		0.49

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: chr4-72618262;