6-22569975-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_138574.4(HDGFL1):c.400G>A(p.Asp134Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,549,298 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 0.000086 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

HDGFL1
NM_138574.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.466

Publications

2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.085749745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDGFL1	NM_138574.4 link	c.400G>A	p.Asp134Asn	missense_variant	Exon 1 of 1	ENST00000510882.4	NP_612641.2	Q5TGJ6A0A140VJK8
LOC105374971	XR_001744025.1 link	n.489-4144G>A		intron_variant	Intron 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HDGFL1	ENST00000510882.4 link	c.400G>A	p.Asp134Asn	missense_variant	Exon 1 of 1	6	NM_138574.4	ENSP00000442129.1	Q5TGJ6
CASC15	ENST00000652081.2 link	n.146-4144G>A		intron_variant	Intron 2 of 7
CASC15	ENST00000846434.1 link	n.433-4144G>A		intron_variant	Intron 3 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD2 exomes

AF:

0.0000202

AC:

AN:

148352

AF XY:

0.0000377

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000859

AC:

AN:

1397310

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

689320

show subpopulations

African (AFR)

AF:

0.000285

AC:

AN:

31570

American (AMR)

AF:

0.0000279

AC:

AN:

35830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.00

AC:

AN:

35836

South Asian (SAS)

AF:

0.00

AC:

AN:

79286

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4598

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1079044

Other (OTH)

AF:

0.0000173

AC:

AN:

57888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000855

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

41388

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2088

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

Alfa

AF:

0.0000708

Hom.:

Bravo

AF:

0.000106

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.400G>A (p.D134N) alteration is located in exon 1 (coding exon 1) of the HDGFL1 gene. This alteration results from a G to A substitution at nucleotide position 400, causing the aspartic acid (D) at amino acid position 134 to be replaced by an asparagine (N). 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

0.087

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.1

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0029

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.43

M_CAP

Benign

0.0086

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

PhyloP100

-0.47

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.94

REVEL

Benign

0.024

Sift

Benign

0.10

Sift4G

Benign

0.49

Polyphen

0.84

Vest4

0.061

MVP

0.24

MPC

0.57

ClinPred

0.028

GERP RS

-1.6

PromoterAI

0.031

Neutral

(source)

Varity_R

0.068

gMVP

0.33

Mutation Taster

=100/0

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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6-22569975-G-A

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