Genetic Variant NM_003071.4:c.2471A>G (chr3-149040062-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003071.4(HLTF):c.2471A>G(p.Lys824Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,459,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K824T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

HLTF
NM_003071.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.93

Publications

4 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10365459).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003071.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLTF	NM_003071.4	MANE Select	c.2471A>G	p.Lys824Arg	missense	Exon 21 of 25	NP_003062.2
HLTF	NM_001318935.2		c.2471A>G	p.Lys824Arg	missense	Exon 21 of 26	NP_001305864.1	Q14527-1
HLTF	NM_139048.3		c.2471A>G	p.Lys824Arg	missense	Exon 21 of 26	NP_620636.1	Q14527-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLTF	ENST00000310053.10	TSL:1 MANE Select	c.2471A>G	p.Lys824Arg	missense	Exon 21 of 25	ENSP00000308944.5	Q14527-1
HLTF	ENST00000392912.6	TSL:1	c.2471A>G	p.Lys824Arg	missense	Exon 21 of 26	ENSP00000376644.2	Q14527-1
HLTF	ENST00000465259.5	TSL:1	c.2468A>G	p.Lys823Arg	missense	Exon 21 of 25	ENSP00000420745.1	A0A0C4DGA6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249782

AF XY:

0.00000740

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1459212

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726012

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.0000432

AC:

AN:

1111028

Other (OTH)

AF:

0.00

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.018

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.69

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.8

PhyloP100

1.9

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.67

REVEL

Benign

0.078

Sift

Benign

0.29

Sift4G

Benign

0.45

Polyphen

0.22

Vest4

0.055

MutPred

0.26

Loss of ubiquitination at K824 (P = 0.0023)

MVP

0.90

MPC

0.15

ClinPred

0.057

GERP RS

-0.087

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.27

Mutation Taster

=95/5

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over