rs778303200

Variant names:

• chr6-22570089-G-A
• rs778303200
• NM_138574.4:c.514G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_138574.4(HDGFL1):​c.514G>A​(p.Glu172Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,540,410 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 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: HDGFL1 NM_138574.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012687296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDGFL1	NM_138574.4	c.514G>A	p.Glu172Lys	missense_variant	Exon 1 of 1	ENST00000510882.4	NP_612641.2
LOC105374971	XR_001744025.1	n.489-4030G>A		intron_variant	Intron 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDGFL1	ENST00000510882.4	c.514G>A	p.Glu172Lys	missense_variant	Exon 1 of 1	6	NM_138574.4	ENSP00000442129.1
CASC15	ENST00000652081.2	n.146-4030G>A		intron_variant	Intron 2 of 7
CASC15	ENST00000846434.1	n.433-4030G>A		intron_variant	Intron 3 of 5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00176

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: 0.000126 AC: 17 AN: 135244 AF XY: 0.0000680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00156

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000936 AC: 13 AN: 1388302 Hom.: 0 Cov.: 32 AF XY: 0.00000731 AC XY: 5 AN XY: 684244

African (AFR) AF: 0.00 AC: 0 AN: 31456

American (AMR) AF: 0.00 AC: 0 AN: 33416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24318

East Asian (EAS) AF: 0.000358 AC: 13 AN: 36336

South Asian (SAS) AF: 0.00 AC: 0 AN: 78304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075622

Other (OTH) AF: 0.00 AC: 0 AN: 57250

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00176 AC: 9 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000895 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514G>A (p.E172K) 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 514, causing the glutamic acid (E) at amino acid position 172 to be replaced by a lysine (K). 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	0.099
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.084
Sift	Benign	0.070	T
Sift4G	Benign	0.28	T
Polyphen		0.97	D
Vest4		0.10
MutPred		0.34		Gain of ubiquitination at E172 (P = 0.0082);
MVP		0.33
MPC		1.2
ClinPred		0.089	T
GERP RS		2.1
Varity_R		0.050
gMVP		0.51
Mutation Taster		=98/2	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: rs778303200; hg19: chr6-22570318;