6-22570138-C-T

Variant names:

• chr6-22570138-C-T
• rs1233077011
• NM_138574.4:c.563C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138574.4(HDGFL1):​c.563C>T​(p.Ala188Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,529,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HDGFL1 NM_138574.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.41
• Publications: 0 publications found

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]

LOC105374971 (HGNC:):

ACMG classification

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=0.11477238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDGFL1	NM_138574.4	c.563C>T	p.Ala188Val	missense_variant	Exon 1 of 1	ENST00000510882.4	NP_612641.2
LOC105374971	XR_001744025.1	n.489-3981C>T		intron_variant	Intron 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDGFL1	ENST00000510882.4	c.563C>T	p.Ala188Val	missense_variant	Exon 1 of 1	6	NM_138574.4	ENSP00000442129.1
CASC15	ENST00000652081.2	n.146-3981C>T		intron_variant	Intron 2 of 7
CASC15	ENST00000846434.1	n.433-3981C>T		intron_variant	Intron 3 of 5

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150632 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000246

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1378890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 679242

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

African (AFR) AF: 0.00 AC: 0 AN: 31258

American (AMR) AF: 0.00 AC: 0 AN: 30906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23396

East Asian (EAS) AF: 0.00 AC: 0 AN: 37334

South Asian (SAS) AF: 0.00 AC: 0 AN: 75948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4326

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1072972

Other (OTH) AF: 0.00 AC: 0 AN: 56942

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150632 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73634

African (AFR) AF: 0.0000246 AC: 1 AN: 40702

American (AMR) AF: 0.00 AC: 0 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67520

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.563C>T (p.A188V) 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 563, causing the alanine (A) at amino acid position 188 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	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-2.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.043
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.087
MutPred		0.33		Gain of catalytic residue at A188 (P = 0.1049);
MVP		0.061
MPC		0.94
ClinPred		0.16	T
GERP RS		0.45
Varity_R		0.023
gMVP		0.22
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs1233077011; hg19: chr6-22570367;