19-15878920-T-C

Variant names:

• chr19-15878920-T-C
• rs4020346
• NM_001082.5:c.1414A>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.1414A>G​(p.Thr472Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.17 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP4F2 NM_001082.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.149
• Publications: 35 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 (MetaRNN=0.011447012).
• BP6: Variant 19-15878920-T-C is Benign according to our data. Variant chr19-15878920-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3059292.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.1414A>G	p.Thr472Ala	missense	Exon 13 of 13	NP_001073.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F2	ENST00000221700.11	TSL:1 MANE Select	c.1414A>G	p.Thr472Ala	missense	Exon 13 of 13	ENSP00000221700.3	P78329-1
	CYP4F2	ENST00000011989.11	TSL:1	c.1414A>G	p.Thr472Ala	missense	Exon 13 of 13	ENSP00000011989.8	A0A0A0MQR0
	CYP4F2	ENST00000886782.1		c.1510A>G	p.Thr504Ala	missense	Exon 14 of 14	ENSP00000556841.1

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 3416 AN: 103230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.0144

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.0373

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.0506

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0303

GnomAD2 exomes AF: 0.236 AC: 33554 AN: 141932 AF XY: 0.226

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.213

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.167 AC: 147828 AN: 887088 Hom.: 4 Cov.: 81 AF XY: 0.157 AC XY: 70028 AN XY: 444656

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

African (AFR) AF: 0.229 AC: 4672 AN: 20404

American (AMR) AF: 0.176 AC: 4917 AN: 27910

Ashkenazi Jewish (ASJ) AF: 0.0820 AC: 1396 AN: 17030

East Asian (EAS) AF: 0.0885 AC: 2241 AN: 25332

South Asian (SAS) AF: 0.0638 AC: 3891 AN: 60994

European-Finnish (FIN) AF: 0.136 AC: 4979 AN: 36626

Middle Eastern (MID) AF: 0.157 AC: 534 AN: 3392

European-Non Finnish (NFE) AF: 0.183 AC: 120137 AN: 657482

Other (OTH) AF: 0.133 AC: 5061 AN: 37918

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0331 AC: 3419 AN: 103298 Hom.: 0 Cov.: 33 AF XY: 0.0383 AC XY: 1904 AN XY: 49714

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

African (AFR) AF: 0.0465 AC: 1201 AN: 25820

American (AMR) AF: 0.0375 AC: 368 AN: 9812

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 42 AN: 2476

East Asian (EAS) AF: 0.0374 AC: 127 AN: 3400

South Asian (SAS) AF: 0.0161 AC: 60 AN: 3732

European-Finnish (FIN) AF: 0.0506 AC: 374 AN: 7386

Middle Eastern (MID) AF: 0.0169 AC: 4 AN: 236

European-Non Finnish (NFE) AF: 0.0246 AC: 1191 AN: 48344

Other (OTH) AF: 0.0300 AC: 42 AN: 1398

⚠️ 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: 0.165 Hom.: 0

ExAC AF: 0.349 AC: 42415

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.30
DANN	Benign	0.35
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.15
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.12
Sift	Benign	0.41	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.15
ClinPred		0.0020	T
GERP RS		0.20
Varity_R		0.058
gMVP		0.56
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4020346; hg19: chr19-15989730; COSMIC: COSV55616098; COSMIC: COSV55616098;