chr1-160881155-T-G

Variant names:

• chr1-160881155-T-G
• NM_017625.3:c.563A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017625.3(ITLN1):​c.563A>C​(p.Gln188Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q188E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ITLN1 NM_017625.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85
• Publications: 0 publications found

Genes affected

ITLN1 (HGNC:18259): (intelectin 1) Enables calcium ion binding activity; identical protein binding activity; and oligosaccharide binding activity. Involved in positive regulation of glucose import; positive regulation of protein phosphorylation; and protein homotrimerization. Located in extracellular exosome. Part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITLN1	NM_017625.3	c.563A>C	p.Gln188Pro	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000326245.4	NP_060095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITLN1	ENST00000326245.4	c.563A>C	p.Gln188Pro	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_017625.3	ENSP00000323587.3
ITLN1	ENST00000464077.1	n.497A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	2
ITLN1	ENST00000487531.1	n.367A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.563A>C (p.Q188P) alteration is located in exon 5 (coding exon 4) of the ITLN1 gene. This alteration results from a A to C substitution at nucleotide position 563, causing the glutamine (Q) at amino acid position 188 to be replaced by a proline (P). 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	Pathogenic	0.67
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0053	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.9
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.026	D
Polyphen		0.91	P
Vest4		0.63
MutPred		0.41		Loss of sheet (P = 0.0181);
MVP		0.30
MPC		0.49
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.92
gMVP		0.81
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr1-160850945;