6-22569583-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138574.4(HDGFL1):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,010 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

HDGFL1
NM_138574.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.44

Publications

0 publications found

Variant links:

Genes affected

HDGFL1 (HGNC:21095): (HDGF like 1) Predicted to enable double-stranded DNA binding activity and transcription coregulator activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HDGFL1 links:

CASC15 (HGNC:28245): (cancer susceptibility 15) This gene produces a long non-coding RNA that may regulate cell proliferation. This RNA is upregulated in hepatocellular carcinoma, where it is thought to function as an oncogene. However, some splice variants of this gene may function as a tumor suppressor in neuroblastoma and other tumor types. Circular RNA variants were observed at this gene. [provided by RefSeq, Dec 2017]

CASC15 links:

LOC105374971 (HGNC:):

LOC105374971 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028549701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDGFL1	NM_138574.4 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 1	ENST00000510882.4	NP_612641.2	Q5TGJ6A0A140VJK8
LOC105374971	XR_001744025.1 link	n.489-4536C>T		intron_variant	Intron 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HDGFL1	ENST00000510882.4 link	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 1	6	NM_138574.4	ENSP00000442129.1	Q5TGJ6
CASC15	ENST00000652081.2 link	n.146-4536C>T		intron_variant	Intron 2 of 7
CASC15	ENST00000846434.1 link	n.433-4536C>T		intron_variant	Intron 3 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152194

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250236

AF XY:

0.0000296

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:

0.0000464

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460816

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1111346

Other (OTH)

AF:

0.0000166

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8C>T (p.A3V) alteration is located in exon 1 (coding exon 1) of the HDGFL1 gene. This alteration results from a C to T substitution at nucleotide position 8, causing the alanine (A) at amino acid position 3 to be replaced by a valine (V). 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

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.14

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0051

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.42

M_CAP

Benign

0.0029

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

-1.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.3

REVEL

Benign

0.021

Sift

Benign

0.55

Sift4G

Benign

0.31

Polyphen

0.038

Vest4

0.074

MutPred

0.20

Loss of relative solvent accessibility (P = 0.0306);

MVP

0.014

MPC

0.56

ClinPred

0.036

GERP RS

-6.7

PromoterAI

0.083

Neutral

(source)

Varity_R

0.022

gMVP

0.10

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

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6-22569583-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over