NM_138574.4:c.574G>A

Variant summary

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

The NM_138574.4(HDGFL1):​c.574G>A​(p.Asp192Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. D192Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

HDGFL1
NM_138574.4 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0510

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]
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]

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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=0.107408464).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HDGFL1NM_138574.4 linkc.574G>A p.Asp192Asn missense_variant Exon 1 of 1 ENST00000510882.4 NP_612641.2 Q5TGJ6A0A140VJK8
LOC105374971XR_001744025.1 linkn.489-3970G>A intron_variant Intron 5 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HDGFL1ENST00000510882.4 linkc.574G>A p.Asp192Asn missense_variant Exon 1 of 1 6 NM_138574.4 ENSP00000442129.1 Q5TGJ6
CASC15ENST00000652081.2 linkn.146-3970G>A intron_variant Intron 2 of 7
CASC15ENST00000846434.1 linkn.433-3970G>A intron_variant Intron 3 of 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.16e-7
AC:
1
AN:
1396510
Hom.:
0
Cov.:
32
AF XY:
0.00000145
AC XY:
1
AN XY:
688914
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32100
American (AMR)
AF:
0.00
AC:
0
AN:
32572
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23978
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37952
South Asian (SAS)
AF:
0.0000128
AC:
1
AN:
78190
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46366
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4616
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1082888
Other (OTH)
AF:
0.00
AC:
0
AN:
57848
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0046
T
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.97
FATHMM_MKL
Benign
0.044
N
LIST_S2
Benign
0.44
T
M_CAP
Benign
0.0091
T
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
L
PhyloP100
0.051
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.55
N
REVEL
Benign
0.097
Sift
Uncertain
0.0020
D
Sift4G
Benign
0.26
T
Polyphen
0.75
P
Vest4
0.048
MutPred
0.14
Gain of glycosylation at T189 (P = 0.1021);
MVP
0.13
MPC
1.2
ClinPred
0.26
T
GERP RS
1.4
Varity_R
0.082
gMVP
0.095
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs752943892; hg19: chr6-22570378; API