Variant 3-121632169-G-A 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>T(p.Pro419Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000924 in 1,613,908 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: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 0 hom. )

Consequence

HCLS1
NM_005335.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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=0.013400584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCLS1	NM_005335.6 linkuse as main transcript	c.1256C>T	p.Pro419Leu	missense_variant	13/14	ENST00000314583.8
HCLS1	NM_001292041.2 linkuse as main transcript	c.1145C>T	p.Pro382Leu	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCLS1	ENST00000314583.8 linkuse as main transcript	c.1256C>T	p.Pro419Leu	missense_variant	13/14	1	NM_005335.6	P1	P14317-1
HCLS1	ENST00000428394.6 linkuse as main transcript	c.1145C>T	p.Pro382Leu	missense_variant	12/13	2
HCLS1	ENST00000473883.5 linkuse as main transcript	n.2059C>T		non_coding_transcript_exon_variant	8/9	2

Frequencies

GnomAD3 genomes

AF:

0.000645

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000742

AC:

184

AN:

248034

Hom.:

AF XY:

0.000774

AC XY:

104

AN XY:

134402

show subpopulations

Gnomad AFR exome

AF:

0.000497

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000953

AC:

1393

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000952

AC XY:

692

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000656

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.000644

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000782

Hom.:

Bravo

AF:

0.000616

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000898

AC:

109

EpiCase

AF:

0.000709

EpiControl

AF:

0.000949

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.1256C>T (p.P419L) alteration is located in exon 13 (coding exon 12) of the HCLS1 gene. This alteration results from a C to T substitution at nucleotide position 1256, causing the proline (P) at amino acid position 419 to be replaced by a leucine (L). 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

0.078

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.58

T;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.065

Sift

Benign

0.044

D;T

Sift4G

Benign

0.36

T;T

Polyphen

0.062

B;B

Vest4

0.096

MVP

0.46

MPC

0.39

ClinPred

0.012

GERP RS

0.47

Varity_R

0.017

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over