19-15878940-G-C

Variant names:

• chr19-15878940-G-C
• rs138905922
• NM_001082.5:c.1398-4C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001082.5(CYP4F2):​c.1398-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000836 in 149,520 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00060 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP4F2 NM_001082.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002930
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0400
• Publications: 4 publications found

Genes affected

CYP4F2 (HGNC:2645): (cytochrome P450 family 4 subfamily F member 2) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum. The enzyme starts the process of inactivating and degrading leukotriene B4, a potent mediator of inflammation. This gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F11, is approximately 16 kb away. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-15878940-G-C is Benign according to our data. Variant chr19-15878940-G-C is described in ClinVar as Benign. ClinVar VariationId is 3038214.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082.5. 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
	CYP4F2	NM_001082.5	MANE Select	c.1398-4C>G		splice_region intron	N/A	NP_001073.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F2	ENST00000221700.11	TSL:1 MANE Select	c.1398-4C>G		splice_region intron	N/A	ENSP00000221700.3	P78329-1
	CYP4F2	ENST00000011989.11	TSL:1	c.1398-4C>G		splice_region intron	N/A	ENSP00000011989.8	A0A0A0MQR0
	CYP4F2	ENST00000886782.1		c.1494-4C>G		splice_region intron	N/A	ENSP00000556841.1

Frequencies

GnomAD3 genomes AF: 0.000837 AC: 125 AN: 149410 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.00346 AC: 858 AN: 247838 AF XY: 0.00223

Gnomad AFR exome AF: 0.0520

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00132

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000605 AC: 880 AN: 1454958 Hom.: 0 Cov.: 39 AF XY: 0.000529 AC XY: 383 AN XY: 724066

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0253 AC: 738 AN: 29162

American (AMR) AF: 0.000991 AC: 44 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00111 AC: 6 AN: 5386

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111046

Other (OTH) AF: 0.000919 AC: 55 AN: 59828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000836 AC: 125 AN: 149520 Hom.: 0 Cov.: 34 AF XY: 0.000807 AC XY: 59 AN XY: 73122

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00306 AC: 119 AN: 38906

American (AMR) AF: 0.000329 AC: 5 AN: 15198

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00205 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CYP4F2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.97
DANN	Benign	0.56
PhyloP100		0.040
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs138905922; hg19: chr19-15989750;