Genetic Variant NM_005335.6:c.997A>T (chr3-121633078-T-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005335.6(HCLS1):c.997A>T(p.Thr333Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000435 in 1,609,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 1 hom. )

Consequence

HCLS1
NM_005335.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0720

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011541605).

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.997A>T	p.Thr333Ser	missense	Exon 11 of 14	NP_005326.3	P14317-1
	HCLS1	NM_001292041.2		c.886A>T	p.Thr296Ser	missense	Exon 10 of 13	NP_001278970.2	E7EVW7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HCLS1	ENST00000314583.8	TSL:1 MANE Select	c.997A>T	p.Thr333Ser	missense	Exon 11 of 14	ENSP00000320176.3	P14317-1
HCLS1	ENST00000909628.1		c.997A>T	p.Thr333Ser	missense	Exon 11 of 14	ENSP00000579687.1
HCLS1	ENST00000909631.1		c.997A>T	p.Thr333Ser	missense	Exon 11 of 14	ENSP00000579690.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151850

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:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000100

AC:

AN:

249474

AF XY:

0.000111

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000453

AC:

AN:

1457352

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

725192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.000721

AC:

AN:

86010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108204

Other (OTH)

AF:

0.0000498

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.000831

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000157

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.30

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.062

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.29

M_CAP

Benign

0.0019

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

-0.072

PrimateAI

Benign

0.34

PROVEAN

Benign

0.34

REVEL

Benign

0.014

Sift

Benign

0.70

Sift4G

Benign

0.73

Polyphen

0.0010

Vest4

0.050

MutPred

0.15

Gain of glycosylation at T333 (P = 0.1101)

MVP

0.64

MPC

0.19

ClinPred

0.018

GERP RS

-1.7

Varity_R

0.012

gMVP

0.14

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over