6-22570102-C-G

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.527C>G(p.Ala176Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,112 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: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

HDGFL1
NM_138574.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.97

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=0.060420036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDGFL1	NM_138574.4 link	c.527C>G	p.Ala176Gly	missense_variant	Exon 1 of 1	ENST00000510882.4	NP_612641.2	Q5TGJ6A0A140VJK8
LOC105374971	XR_001744025.1 link	n.489-4017C>G		intron_variant	Intron 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HDGFL1	ENST00000510882.4 link	c.527C>G	p.Ala176Gly	missense_variant	Exon 1 of 1	6	NM_138574.4	ENSP00000442129.1	Q5TGJ6
CASC15	ENST00000652081.2 link	n.146-4017C>G		intron_variant	Intron 2 of 7
CASC15	ENST00000846434.1 link	n.433-4017C>G		intron_variant	Intron 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1383112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

681250

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31484

American (AMR)

AF:

0.00

AC:

AN:

32596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23942

East Asian (EAS)

AF:

0.00

AC:

AN:

36486

South Asian (SAS)

AF:

0.00

AC:

AN:

77346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1072980

Other (OTH)

AF:

0.00

AC:

AN:

57006

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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 18, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.527C>G (p.A176G) alteration is located in exon 1 (coding exon 1) of the HDGFL1 gene. This alteration results from a C to G substitution at nucleotide position 527, causing the alanine (A) at amino acid position 176 to be replaced by a glycine (G). 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

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.085

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0031

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0064

LIST_S2

Benign

0.22

M_CAP

Benign

0.0026

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

-3.0

PrimateAI

Benign

0.44

PROVEAN

Benign

0.050

REVEL

Benign

0.0010

Sift

Benign

0.21

Sift4G

Benign

0.40

Polyphen

0.0040

Vest4

0.063

MutPred

0.26

Gain of relative solvent accessibility (P = 0.0023);

MVP

0.030

MPC

0.96

ClinPred

0.083

GERP RS

-0.88

Varity_R

0.030

gMVP

0.25

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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6-22570102-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over