Genetic Variant HLTF:p.Val927Leu (chr3-149039066-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003071.4(HLTF):c.2779G>T(p.Val927Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000316 in 1,581,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

HLTF
NM_003071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66

Variant links:

Genes affected

HLTF (HGNC:11099): (helicase like transcription factor) This gene encodes a member of the SWI/SNF family. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein contains a RING finger DNA binding motif. Two transcript variants encoding the same protein have been found for this gene. However, use of an alternative translation start site produces an isoform that is truncated at the N-terminus compared to the full-length protein. [provided by RefSeq, Jul 2008]

HLTF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLTF	NM_003071.4 link	c.2779G>T	p.Val927Leu	missense_variant	Exon 23 of 25	ENST00000310053.10	NP_003062.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLTF	ENST00000310053.10 link	c.2779G>T	p.Val927Leu	missense_variant	Exon 23 of 25	1	NM_003071.4	ENSP00000308944.5		Q14527-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152084

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

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1429576

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710384

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

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:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

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

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2779G>T (p.V927L) alteration is located in exon 23 (coding exon 23) of the HLTF gene. This alteration results from a G to T substitution at nucleotide position 2779, causing the valine (V) at amino acid position 927 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

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;T;T;T;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;.;.;D;D

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.5

.;M;M;M;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.3

N;N;N;N;N

REVEL

Pathogenic

0.71

Sift

Benign

0.099

T;T;T;T;T

Sift4G

Benign

0.082

T;T;T;T;.

Polyphen

1.0

.;D;D;D;.

Vest4

0.84

MutPred

0.74

.;Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);.;

MVP

0.87

MPC

0.72

ClinPred

0.95

GERP RS

6.0

Varity_R

0.18

gMVP

0.70

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