1-45640292-T-C

Variant names:

• chr1-45640292-T-C
• NM_021639.5:c.662A>G

Variant summary

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

The NM_021639.5(GPBP1L1):​c.662A>G​(p.His221Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GPBP1L1 NM_021639.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

Genes affected

GPBP1L1 (HGNC:28843): (GC-rich promoter binding protein 1 like 1) Predicted to enable DNA binding activity and RNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.085728526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPBP1L1	NM_021639.5	c.662A>G	p.His221Arg	missense_variant	Exon 8 of 13	ENST00000355105.8	NP_067652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPBP1L1	ENST00000355105.8	c.662A>G	p.His221Arg	missense_variant	Exon 8 of 13	1	NM_021639.5	ENSP00000347224.3
GPBP1L1	ENST00000290795.7	c.662A>G	p.His221Arg	missense_variant	Exon 7 of 12	5		ENSP00000290795.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.662A>G (p.H221R) alteration is located in exon 8 (coding exon 5) of the GPBP1L1 gene. This alteration results from a A to G substitution at nucleotide position 662, causing the histidine (H) at amino acid position 221 to be replaced by an arginine (R). 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	0.090
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	.;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.046
Sift	Benign	0.34	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0	B;B
Vest4		0.26
MutPred		0.14		Loss of ubiquitination at K226 (P = 0.0142);Loss of ubiquitination at K226 (P = 0.0142);
MVP		0.076
MPC		0.13
ClinPred		0.30	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.14

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: chr1-46105964;