chr19-4494212-G-A

Variant names:

• chr19-4494212-G-A
• rs1018908486
• NM_001001520.3:c.961G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001001520.3(HDGFL2):​c.961G>A​(p.Glu321Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000305 in 1,312,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: HDGFL2 NM_001001520.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.74
• Publications: 0 publications found

Genes affected

HDGFL2 (HGNC:14680): (HDGF like 2) This gene encodes a member of the hepatoma-derived growth factor (HDGF) family. The protein includes an N-terminal PWWP domain that binds to methyl-lysine-containing histones, with specific binding of this protein to tri-methylated lysines 36 and 79 of histone H3, and di- and tri-methylated lysine 20 of histone H4. The protein functions in LEDGF/p75-independent HIV-1 replication by determining HIV-1 integration site selection. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27431977).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001520.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDGFL2	NM_001001520.3	MANE Select	c.961G>A	p.Glu321Lys	missense	Exon 9 of 16	NP_001001520.1	Q7Z4V5-1
	HDGFL2	NM_001348169.2		c.1033G>A	p.Glu345Lys	missense	Exon 9 of 16	NP_001335098.1
	HDGFL2	NM_032631.4		c.961G>A	p.Glu321Lys	missense	Exon 9 of 16	NP_116020.1	Q7Z4V5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDGFL2	ENST00000616600.5	TSL:1 MANE Select	c.961G>A	p.Glu321Lys	missense	Exon 9 of 16	ENSP00000483345.1	Q7Z4V5-1
	HDGFL2	ENST00000621835.4	TSL:1	c.961G>A	p.Glu321Lys	missense	Exon 9 of 16	ENSP00000483702.1	Q7Z4V5-2
	HDGFL2	ENST00000901364.1		c.961G>A	p.Glu321Lys	missense	Exon 9 of 17	ENSP00000571423.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000323 AC: 2 AN: 61882 AF XY: 0.0000594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000180

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: 0.00000305 AC: 4 AN: 1312518 Hom.: 0 Cov.: 35 AF XY: 0.00000467 AC XY: 3 AN XY: 642080

African (AFR) AF: 0.00 AC: 0 AN: 27044

American (AMR) AF: 0.0000931 AC: 2 AN: 21486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20026

East Asian (EAS) AF: 0.00 AC: 0 AN: 32440

South Asian (SAS) AF: 0.00 AC: 0 AN: 67094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5094

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1044146

Other (OTH) AF: 0.0000185 AC: 1 AN: 54132

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.7
PrimateAI	Pathogenic	0.95	D
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.17		Gain of methylation at E321 (P = 0.0058)
MVP		0.15
ClinPred		0.76	D
GERP RS		4.4
Varity_R		0.36
gMVP		0.27
Mutation Taster		=91/9	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: rs1018908486; hg19: chr19-4494209;