19-4493812-C-G

Variant names:

• chr19-4493812-C-G
• rs770893579
• NM_001001520.3:c.788C>G

Variant summary

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

The NM_001001520.3(HDGFL2):​c.788C>G​(p.Ser263Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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. S263F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: HDGFL2 NM_001001520.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1195333).

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.788C>G	p.Ser263Cys	missense	Exon 7 of 16	NP_001001520.1	Q7Z4V5-1
	HDGFL2	NM_001348169.2		c.860C>G	p.Ser287Cys	missense	Exon 7 of 16	NP_001335098.1
	HDGFL2	NM_032631.4		c.788C>G	p.Ser263Cys	missense	Exon 7 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.788C>G	p.Ser263Cys	missense	Exon 7 of 16	ENSP00000483345.1	Q7Z4V5-1
	HDGFL2	ENST00000621835.4	TSL:1	c.788C>G	p.Ser263Cys	missense	Exon 7 of 16	ENSP00000483702.1	Q7Z4V5-2
	HDGFL2	ENST00000901364.1		c.788C>G	p.Ser263Cys	missense	Exon 7 of 17	ENSP00000571423.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.3
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.052	T
Polyphen		0.89	P
Vest4		0.25
MutPred		0.36		Loss of phosphorylation at S263 (P = 2e-04)
MVP		0.10
ClinPred		0.45	T
GERP RS		2.7
Varity_R		0.074
gMVP		0.14
Mutation Taster		=96/4	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: rs770893579; hg19: chr19-4493809;