3-121632491-C-T

Variant names:

• chr3-121632491-C-T
• rs2070180
• NM_005335.6:c.1081G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005335.6(HCLS1):​c.1081G>A​(p.Glu361Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,613,780 control chromosomes in the GnomAD database, including 59,047 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4219 hom., cov: 31)
  • Exomes 𝑓: 0.27 (54828 hom.)
• Consequence: HCLS1 NM_005335.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 34 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053710043).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005335.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCLS1	NM_005335.6	MANE Select	c.1081G>A	p.Glu361Lys	missense	Exon 12 of 14	NP_005326.3	P14317-1
	HCLS1	NM_001292041.2		c.970G>A	p.Glu324Lys	missense	Exon 11 of 13	NP_001278970.2	E7EVW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCLS1	ENST00000314583.8	TSL:1 MANE Select	c.1081G>A	p.Glu361Lys	missense	Exon 12 of 14	ENSP00000320176.3	P14317-1
	HCLS1	ENST00000909628.1		c.1081G>A	p.Glu361Lys	missense	Exon 12 of 14	ENSP00000579687.1
	HCLS1	ENST00000909631.1		c.1081G>A	p.Glu361Lys	missense	Exon 12 of 14	ENSP00000579690.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33393 AN: 151928 Hom.: 4220 Cov.: 31

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0828

Gnomad SAS AF: 0.0981

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.213 AC: 53017 AN: 248910 AF XY: 0.212

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.0789

Gnomad FIN exome AF: 0.316

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.265 AC: 387460 AN: 1461732 Hom.: 54828 Cov.: 75 AF XY: 0.260 AC XY: 189054 AN XY: 727154

African (AFR) AF: 0.141 AC: 4706 AN: 33480

American (AMR) AF: 0.123 AC: 5496 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 5137 AN: 26136

East Asian (EAS) AF: 0.0884 AC: 3511 AN: 39700

South Asian (SAS) AF: 0.109 AC: 9436 AN: 86190

European-Finnish (FIN) AF: 0.310 AC: 16537 AN: 53354

Middle Eastern (MID) AF: 0.160 AC: 925 AN: 5768

European-Non Finnish (NFE) AF: 0.295 AC: 327482 AN: 1111990

Other (OTH) AF: 0.236 AC: 14230 AN: 60392

GnomAD4 genome AF: 0.220 AC: 33386 AN: 152048 Hom.: 4219 Cov.: 31 AF XY: 0.214 AC XY: 15872 AN XY: 74318

African (AFR) AF: 0.145 AC: 6028 AN: 41498

American (AMR) AF: 0.144 AC: 2208 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 692 AN: 3468

East Asian (EAS) AF: 0.0829 AC: 428 AN: 5160

South Asian (SAS) AF: 0.0981 AC: 472 AN: 4810

European-Finnish (FIN) AF: 0.312 AC: 3292 AN: 10558

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19410 AN: 67960

Other (OTH) AF: 0.209 AC: 440 AN: 2106

Alfa AF: 0.253 Hom.: 17367

Bravo AF: 0.209

TwinsUK AF: 0.293 AC: 1085

ALSPAC AF: 0.297 AC: 1146

ESP6500AA AF: 0.150 AC: 662

ESP6500EA AF: 0.287 AC: 2464

ExAC AF: 0.216 AC: 26253

Asia WGS AF: 0.110 AC: 386 AN: 3478

EpiCase AF: 0.272

EpiControl AF: 0.266

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.084
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.071
Sift	Benign	0.071	T
Sift4G	Benign	0.32	T
Polyphen		0.93	P
Vest4		0.18
MPC		0.23
ClinPred		0.019	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.37
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070180; hg19: chr3-121351338; COSMIC: COSV57522740; COSMIC: COSV57522740;