3-121632468-G-GGGCTCAGGCTCA

Position:

• chr3-121632468-G-GGGCTCAGGCTCA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005335.6(HCLS1):​c.1092_1103dupTGAGCCTGAGCC​(p.Pro368_Glu369insGluProGluPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,612,982 control chromosomes in the GnomAD database, including 45,549 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3974 hom., cov: 25)
  • Exomes 𝑓: 0.23 (41575 hom.)
• Consequence: HCLS1 NM_005335.6 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0890

Genes affected

HCLS1 (HGNC:4844): (hematopoietic cell-specific Lyn substrate 1) Enables RNA polymerase II-specific DNA-binding transcription factor binding activity and protein kinase binding activity. Involved in several processes, including positive regulation of intracellular signal transduction; positive regulation of protein phosphorylation; and regulation of transcription, DNA-templated. Located in cytosol; nucleus; and plasma membrane. Part of transcription regulator complex. [provided by Alliance of Genome Resources, Apr 2022]

HCLS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 3-121632468-G-GGGCTCAGGCTCA is Benign according to our data. Variant chr3-121632468-G-GGGCTCAGGCTCA is described in ClinVar as [Benign]. Clinvar id is 1291285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCLS1	NM_005335.6	c.1092_1103dupTGAGCCTGAGCC	p.Pro368_Glu369insGluProGluPro	disruptive_inframe_insertion	12/14	ENST00000314583.8	NP_005326.3
HCLS1	NM_001292041.2	c.981_992dupTGAGCCTGAGCC	p.Pro331_Glu332insGluProGluPro	disruptive_inframe_insertion	11/13		NP_001278970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCLS1	ENST00000314583.8	c.1092_1103dupTGAGCCTGAGCC	p.Pro368_Glu369insGluProGluPro	disruptive_inframe_insertion	12/14	1	NM_005335.6	ENSP00000320176.3

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33125 AN: 151376 Hom.: 3976 Cov.: 25

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.234 AC: 341474 AN: 1461488 Hom.: 41575 Cov.: 63 AF XY: 0.234 AC XY: 170396 AN XY: 727082

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.301

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.256

GnomAD4 genome AF: 0.219 AC: 33122 AN: 151494 Hom.: 3974 Cov.: 25 AF XY: 0.216 AC XY: 16012 AN XY: 73990

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.446

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.250

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 15022330) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs150627065; hg19: chr3-121351315;