chr4-71756765-C-G

Position:

• chr4-71756765-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000583.4(GC):​c.981G>C​(p.Glu327Asp) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GC NM_000583.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.132

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08366695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GC	NM_000583.4	c.981G>C	p.Glu327Asp	missense_variant	8/13	ENST00000273951.13
GC	NM_001204307.1	c.1038G>C	p.Glu346Asp	missense_variant	9/14
GC	NM_001204306.1	c.981G>C	p.Glu327Asp	missense_variant	9/14
GC	XM_006714177.3	c.981G>C	p.Glu327Asp	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GC	ENST00000273951.13	c.981G>C	p.Glu327Asp	missense_variant	8/13	1	NM_000583.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

May 13, 2024

The c.981G>C (p.E327D) alteration is located in exon 8 (coding exon 8) of the GC gene. This alteration results from a G to C substitution at nucleotide position 981, causing the glutamic acid (E) at amino acid position 327 to be replaced by an aspartic acid (D). 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	0.095
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.4
DANN	Benign	0.84
DEOGEN2	Benign	0.095	T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.14	N;N;N
REVEL	Benign	0.070
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.0040	.;.;B
Vest4		0.078
MutPred		0.24		Loss of catalytic residue at E327 (P = 0.0423);.;Loss of catalytic residue at E327 (P = 0.0423);
MVP		0.47
MPC		0.047
ClinPred		0.041	T
GERP RS		2.8
Varity_R		0.10
gMVP		0.18

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: chr4-72622482;