Variant chr3-121632518-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_005335.6(HCLS1):c.1054C>T(p.Leu352Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,612,378 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

HCLS1
NM_005335.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.140

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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030876637).

BP6

Variant 3-121632518-G-A is Benign according to our data. Variant chr3-121632518-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3104475.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCLS1	NM_005335.6 linkuse as main transcript	c.1054C>T	p.Leu352Phe	missense_variant	12/14	ENST00000314583.8
HCLS1	NM_001292041.2 linkuse as main transcript	c.943C>T	p.Leu315Phe	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCLS1	ENST00000314583.8 linkuse as main transcript	c.1054C>T	p.Leu352Phe	missense_variant	12/14	1	NM_005335.6	P1	P14317-1
HCLS1	ENST00000428394.6 linkuse as main transcript	c.943C>T	p.Leu315Phe	missense_variant	11/13	2
HCLS1	ENST00000473883.5 linkuse as main transcript	n.1857C>T		non_coding_transcript_exon_variant	7/9	2
HCLS1	ENST00000495491.5 linkuse as main transcript	c.*369C>T		3_prime_UTR_variant, NMD_transcript_variant	11/11	2			P14317-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000966

AC:

AN:

248372

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

134550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461284

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000986

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151094

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73784

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.20

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.059

Sift

Benign

0.19

T;T

Sift4G

Benign

0.78

T;T

Polyphen

0.060

B;B

Vest4

0.042

MVP

0.33

MPC

0.34

ClinPred

0.026

GERP RS

-4.2

Varity_R

0.041

gMVP

0.12

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

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