Genetic Variant NM_003071.4:c.2902G>A (chr3-149032348-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003071.4(HLTF):c.2902G>A(p.Glu968Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLTF
NM_003071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.76

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLTF	NM_003071.4 link	c.2902G>A	p.Glu968Lys	missense_variant	Exon 25 of 25	ENST00000310053.10	NP_003062.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HLTF	ENST00000310053.10 link	c.2902G>A	p.Glu968Lys	missense_variant	Exon 25 of 25	1	NM_003071.4	ENSP00000308944.5	Q14527-1
HLTF	ENST00000392912.6 link	c.2902G>A	p.Glu968Lys	missense_variant	Exon 25 of 26	1		ENSP00000376644.2	Q14527-1
HLTF	ENST00000465259.5 link	c.2899G>A	p.Glu967Lys	missense_variant	Exon 25 of 25	1		ENSP00000420745.1	A0A0C4DGA6
HLTF	ENST00000494055.5 link	c.2902G>A	p.Glu968Lys	missense_variant	Exon 25 of 26	2		ENSP00000420429.1	Q14527-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.05e-7

AC:

AN:

1418982

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

706162

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.17e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2902G>A (p.E968K) alteration is located in exon 25 (coding exon 25) of the HLTF gene. This alteration results from a G to A substitution at nucleotide position 2902, causing the glutamic acid (E) at amino acid position 968 to be replaced by a lysine (K). 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

0.82

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

.;T;T;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;.;.;D

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.8

.;M;M;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.74

MutPred

0.51

.;Gain of MoRF binding (P = 0.002);Gain of MoRF binding (P = 0.002);Gain of MoRF binding (P = 0.002);

MVP

0.83

MPC

0.77

ClinPred

0.99

GERP RS

5.8

Varity_R

0.35

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over