1-53509927-G-A

Position:

• chr1-53509927-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001367484.1(GLIS1):​c.1984C>T​(p.Pro662Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000867 in 1,153,830 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: 33)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: GLIS1 NM_001367484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.860

Genes affected

GLIS1 (HGNC:29525): (GLIS family zinc finger 1) GLIS1 is a GLI (MIM 165220)-related Kruppel-like zinc finger protein that functions as an activator and repressor of transcription (Kim et al., 2002 [PubMed 12042312]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06664243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS1	NM_001367484.1	c.1984C>T	p.Pro662Ser	missense_variant	9/11	ENST00000628545.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS1	ENST00000628545.2	c.1984C>T	p.Pro662Ser	missense_variant	9/11	5	NM_001367484.1	P2
GLIS1	ENST00000312233.4	c.1459C>T	p.Pro487Ser	missense_variant	8/10	2		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.67e-7 AC: 1 AN: 1153830 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 551620

Gnomad4 AFR exome AF: 0.0000402

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 23, 2023

The c.1459C>T (p.P487S) alteration is located in exon 8 (coding exon 6) of the GLIS1 gene. This alteration results from a C to T substitution at nucleotide position 1459, causing the proline (P) at amino acid position 487 to be replaced by a serine (S). 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	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Uncertain	0.97
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.98	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.31	N;.
REVEL	Benign	0.054
Sift	Benign	0.25	T;.
Sift4G	Benign	0.80	T;T
Polyphen		0.0	B;.
Vest4		0.13
MutPred		0.37		Gain of phosphorylation at P487 (P = 0.0085);.;
MVP		0.48
MPC		0.051
ClinPred		0.10	T
GERP RS		-0.60
Varity_R		0.032
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs1644281421; hg19: chr1-53975600;