NM_002619.4:c.216G>C

Variant names:

• chr4-73981419-C-G
• rs2233648
• NM_002619.4:c.216G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002619.4(PF4):​c.216G>C​(p.Leu72Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,614,080 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (62 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (89 hom.)
• Consequence: PF4 NM_002619.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00007323
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.172
• Publications: 2 publications found

Genes affected

PF4 (HGNC:8861): (platelet factor 4) This gene encodes a member of the CXC chemokine family. This chemokine is released from the alpha granules of activated platelets in the form of a homotetramer which has high affinity for heparin and is involved in platelet aggregation. This protein is chemotactic for numerous other cell type and also functions as an inhibitor of hematopoiesis, angiogenesis and T-cell function. The protein also exhibits antimicrobial activity against Plasmodium falciparum. [provided by RefSeq, Oct 2014]

ENSG00000288796 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 4-73981419-C-G is Benign according to our data. Variant chr4-73981419-C-G is described in ClinVar as Benign. ClinVar VariationId is 778143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.172 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002619.4. 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
	PF4	NM_002619.4	MANE Select	c.216G>C	p.Leu72Leu	splice_region synonymous	Exon 2 of 3	NP_002610.1	P02776
	PF4	NM_001363352.1		c.243G>C	p.Leu81Leu	splice_region synonymous	Exon 2 of 3	NP_001350281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PF4	ENST00000296029.4	TSL:1 MANE Select	c.216G>C	p.Leu72Leu	splice_region synonymous	Exon 2 of 3	ENSP00000296029.3	P02776
	ENSG00000288796	ENST00000693342.1		c.492G>C	p.Leu164Leu	splice_region synonymous	Exon 4 of 5	ENSP00000510492.1	A0A8I5KW61
	PF4	ENST00000687529.1		n.*247G>C		splice_region non_coding_transcript_exon	Exon 2 of 3	ENSP00000508485.1	A0A8I5QJ57

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2958 AN: 152126 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00891

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00536 AC: 1347 AN: 251384 AF XY: 0.00403

Gnomad AFR exome AF: 0.0704

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00217 AC: 3178 AN: 1461838 Hom.: 89 Cov.: 32 AF XY: 0.00192 AC XY: 1399 AN XY: 727220

African (AFR) AF: 0.0715 AC: 2393 AN: 33466

American (AMR) AF: 0.00429 AC: 192 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5766

European-Non Finnish (NFE) AF: 0.000178 AC: 198 AN: 1111992

Other (OTH) AF: 0.00528 AC: 319 AN: 60392

GnomAD4 genome AF: 0.0195 AC: 2963 AN: 152242 Hom.: 62 Cov.: 33 AF XY: 0.0185 AC XY: 1379 AN XY: 74434

African (AFR) AF: 0.0665 AC: 2761 AN: 41536

American (AMR) AF: 0.00890 AC: 136 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68010

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.00518 Hom.: 2

Bravo AF: 0.0232

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.57
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.0060
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: rs2233648; hg19: chr4-74847136;