Variant 3-121632169-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005335.6(HCLS1):c.1256C>G(p.Pro419Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

HCLS1
NM_005335.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.10

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.06316143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCLS1	NM_005335.6 link	c.1256C>G	p.Pro419Arg	missense_variant	Exon 13 of 14	ENST00000314583.8	NP_005326.3	P14317-1
HCLS1	NM_001292041.2 link	c.1145C>G	p.Pro382Arg	missense_variant	Exon 12 of 13		NP_001278970.2	P14317

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCLS1	ENST00000314583.8 link	c.1256C>G	p.Pro419Arg	missense_variant	Exon 13 of 14	1	NM_005335.6	ENSP00000320176.3	P14317-1
HCLS1	ENST00000428394.6 link	c.1145C>G	p.Pro382Arg	missense_variant	Exon 12 of 13	2		ENSP00000387645.2	E7EVW7
HCLS1	ENST00000473883.5 link	n.2059C>G		non_coding_transcript_exon_variant	Exon 8 of 9	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248034

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134402

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

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:

0.0000828

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.4

DANN

Benign

0.61

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.0025

MetaRNN

Benign

0.063

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.078

Sift

Benign

0.097

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0

B;B

Vest4

0.10

MutPred

0.38

Gain of methylation at P419 (P = 0.0308);.;

MVP

0.45

MPC

0.49

ClinPred

0.039

GERP RS

0.47

Varity_R

0.021

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over