chr1-156745332-G-T

Variant names:

• chr1-156745332-G-T
• rs372321208
• NM_004494.3:c.129C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004494.3(HDGF):​c.129C>A​(p.Asn43Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: HDGF NM_004494.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

Genes affected

HDGF (HGNC:4856): (heparin binding growth factor) This gene encodes a member of the hepatoma-derived growth factor family. The encoded protein has mitogenic and DNA-binding activity and may play a role in cellular proliferation and differentiation. High levels of expression of this gene enhance the growth of many tumors. This gene was thought initially to be located on chromosome X; however, that location has been determined to correspond to a related pseudogene. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDGF	NM_004494.3	c.129C>A	p.Asn43Lys	missense_variant	Exon 2 of 6	ENST00000357325.10	NP_004485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDGF	ENST00000357325.10	c.129C>A	p.Asn43Lys	missense_variant	Exon 2 of 6	1	NM_004494.3	ENSP00000349878.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000902 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.177C>A (p.N59K) alteration is located in exon 2 (coding exon 2) of the HDGF gene. This alteration results from a C to A substitution at nucleotide position 177, causing the asparagine (N) at amino acid position 59 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.4	L;L;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.14	T;T;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.70
MutPred		0.46		Loss of ubiquitination at K39 (P = 0.055);Loss of ubiquitination at K39 (P = 0.055);.;.;
MVP		0.75
MPC		1.3
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.78
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs372321208; hg19: chr1-156715124;