NM_000583.4:c.59-3707G>T

Variant names:

• chr4-71773107-C-A
• rs16847015
• NM_000583.4:c.59-3707G>T

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_000583.4(GC):c.59-3707G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0876 (AC=13,310) in the gnomAD database across 151,994 control chromosomes, including 835 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.225. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.088 (835 hom., cov: 33)
• Consequence: GC NM_000583.4 intron
• Predictors: AlphaGenome AVI: 5: Benign
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.457
• Publications: 12 publications found

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2253 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000583.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GC NM_000583.4	MANE Select	c.59-3707G>T	intron	Intron 1 of 12	Prot: NP_000574.2
	GC NM_001204307.1		c.116-3707G>T	intron	Intron 2 of 13	Prot: NP_001191236.1 UniProt:
	GC NM_001204306.1		c.59-3707G>T	intron	Intron 2 of 13	Prot: NP_001191235.1 UniProt:

GC NM_000583.4

MANE Select

HGVSc / HGVSpc.59-3707G>T

Exon rankIntron 1 of 12

intron

Prot: NP_000574.2

GC NM_001204307.1

HGVSc / HGVSpc.116-3707G>T

Exon rankIntron 2 of 13

intron

Prot: NP_001191236.1UniProt: P02774-3

GC NM_001204306.1

HGVSc / HGVSpc.59-3707G>T

Exon rankIntron 2 of 13

intron

Prot: NP_001191235.1UniProt: P02774-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GC ENST00000273951.13	TSL:1MANE Select	c.59-3707G>T	intron	Intron 1 of 12	Prot: ENSP00000273951.8 UniProt:
	GC ENST00000504199.5	TSL:1	c.116-3707G>T	intron	Intron 2 of 13	Prot: ENSP00000421725.1 UniProt:
	GC ENST00000513476.5	TSL:5	c.59-3707G>T	intron	Intron 1 of 11	Prot: ENSP00000426683.1 UniProt:

GC ENST00000273951.13

TSL:1MANE Select

HGVSc / HGVSpc.59-3707G>T

Exon rankIntron 1 of 12

intron

Prot: ENSP00000273951.8UniProt: P02774-1

GC ENST00000504199.5

TSL:1

HGVSc / HGVSpc.116-3707G>T

Exon rankIntron 2 of 13

intron

Prot: ENSP00000421725.1UniProt: P02774-3

GC ENST00000513476.5

TSL:5

HGVSc / HGVSpc.59-3707G>T

Exon rankIntron 1 of 11

intron

Prot: ENSP00000426683.1UniProt: D6RF35

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0876	AC:13299	Hom:830	AN:151876	Cov:33
GnomAD4 genome	AF: 0.0876	AC:13310	Hom:835	AN:151994	Cov:33
TOPMed (Bravo)	AF: 0.0981	AC:25974	Hom:1764	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0629	AC:3833	Hom:221	AN:60957	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0756	AC:177	Hom:3	AN:2340	Cov:
ChinaMAP Phase 1	AF: 0.223	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0367	AC:11	Hom:	AN:300	Cov:
Korea4K (4,157 Koreans)	AF: 0.206	AC:1486	Hom:	AN:7226	Cov:
Qatari Genome	AF: 0.131	AC:23	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.193	AC:23494	Hom:2273	AN:121766	Cov:
Turkish Variome	AF: 0.0757	AC:117	Hom:7	AN:1546	Cov:
UK10K	AF: 0.0468	AC:354	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.227	AC:2030	Hom:239	AN:8960	Cov:

Showing 13 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	4.6
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.8
DANN	Benign	0.76
GPN-Star LLR	N/A	0.92
GPN-Star score	N/A	-0.92
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.46

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs16847015;

hg19: chr4-72638824;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar