rs1143704

chr15-51218505-T-Achr15-51218505-T-Cchr15-51218505-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000103.4(CYP19A1):c.743+36A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 1,589,230 control chromosomes in the GnomAD database, including 198,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14716 hom., cov: 32)
  • Exomes 𝑓: 0.50 (183933 hom.)
• Consequence: CYP19A1 NM_000103.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.184

Genes affected

CYP19A1 (HGNC:2594): (cytochrome P450 family 19 subfamily A member 1) 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 and catalyzes the last steps of estrogen biosynthesis. Mutations in this gene can result in either increased or decreased aromatase activity; the associated phenotypes suggest that estrogen functions both as a sex steroid hormone and in growth or differentiation. Alternative promoter use and alternative splicing results in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]

MIR4713HG (HGNC:53124): (MIR4713 host gene)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.10286E-5).
• BP6: Variant 15-51218505-T-A is Benign according to our data. Variant chr15-51218505-T-A is described in ClinVar as [Benign]. Clinvar id is 1168854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP19A1	NM_000103.4	c.743+36A>T		intron_variant		ENST00000396402.6
MIR4713HG	NR_146310.1	n.195-59478T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP19A1	ENST00000396402.6	c.743+36A>T		intron_variant		1	NM_000103.4	P1
MIR4713HG	ENST00000559909.1	n.195-59478T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64367 AN: 151910 Hom.: 14718 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.444

GnomAD3 exomes AF: 0.450 AC: 97867 AN: 217604 Hom.: 23073 AF XY: 0.455 AC XY: 53133 AN XY: 116844

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.517

Gnomad SAS exome AF: 0.355

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.501 AC: 719591 AN: 1437200 Hom.: 183933 Cov.: 39 AF XY: 0.498 AC XY: 354910 AN XY: 712698

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.327

Gnomad4 ASJ exome AF: 0.531

Gnomad4 EAS exome AF: 0.475

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.501

Gnomad4 NFE exome AF: 0.528

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.423 AC: 64382 AN: 152030 Hom.: 14716 Cov.: 32 AF XY: 0.420 AC XY: 31179 AN XY: 74306

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.540

Gnomad4 EAS AF: 0.497

Gnomad4 SAS AF: 0.362

Gnomad4 FIN AF: 0.494

Gnomad4 NFE AF: 0.526

Gnomad4 OTH AF: 0.442

Alfa AF: 0.491 Hom.: 3498

Bravo AF: 0.409

TwinsUK AF: 0.541 AC: 2007

ALSPAC AF: 0.525 AC: 2022

ESP6500AA AF: 0.246 AC: 1081

ESP6500EA AF: 0.519 AC: 4452

ExAC AF: 0.430 AC: 51739

Asia WGS AF: 0.379 AC: 1318 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16882736) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	6.3
Dann	Benign	0.83
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.000041	T
MutationTaster	Benign	1.0	P;P;P;P
GERP RS		-3.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs1143704; hg19: chr15-51510702; COSMIC: COSV53058074; COSMIC: COSV53058074;