rs35636804

Variant names:

• chr15-51208769-C-A
• rs35636804
• NM_000103.4:c.*2039G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000103.4(CYP19A1):​c.*2039G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 128,802 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (91 hom., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP19A1 NM_000103.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.852
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-51208769-C-A is Benign according to our data. Variant chr15-51208769-C-A is described in ClinVar as Benign. ClinVar VariationId is 316449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0329 (4237/128802) while in subpopulation AMR AF = 0.0491 (560/11404). AF 95% confidence interval is 0.0457. There are 91 homozygotes in GnomAd4. There are 1965 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 91 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000103.4. 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
	CYP19A1	NM_000103.4	MANE Select	c.*2039G>T		3_prime_UTR	Exon 10 of 10	NP_000094.2
	CYP19A1	NM_001347248.1		c.*2039G>T		3_prime_UTR	Exon 10 of 10	NP_001334177.1	P11511-1
	CYP19A1	NM_001347249.2		c.*2039G>T		3_prime_UTR	Exon 10 of 10	NP_001334178.1	P11511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP19A1	ENST00000396402.6	TSL:1 MANE Select	c.*2039G>T		3_prime_UTR	Exon 10 of 10	ENSP00000379683.1	P11511-1
	MIR4713HG	ENST00000559909.1	TSL:4	n.195-69214C>A		intron	N/A
	MIR4713HG	ENST00000805692.1		n.279-69214C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 4241 AN: 128706 Hom.: 91 Cov.: 22

Gnomad AFR AF: 0.00893

Gnomad AMI AF: 0.0282

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0273

Gnomad EAS AF: 0.000552

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0468

Gnomad OTH AF: 0.0448

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0329 AC: 4237 AN: 128802 Hom.: 91 Cov.: 22 AF XY: 0.0321 AC XY: 1965 AN XY: 61154

African (AFR) AF: 0.00891 AC: 313 AN: 35120

American (AMR) AF: 0.0491 AC: 560 AN: 11404

Ashkenazi Jewish (ASJ) AF: 0.0273 AC: 88 AN: 3220

East Asian (EAS) AF: 0.000553 AC: 2 AN: 3616

South Asian (SAS) AF: 0.0195 AC: 67 AN: 3436

European-Finnish (FIN) AF: 0.0263 AC: 190 AN: 7220

Middle Eastern (MID) AF: 0.0759 AC: 17 AN: 224

European-Non Finnish (NFE) AF: 0.0468 AC: 2899 AN: 61950

Other (OTH) AF: 0.0437 AC: 77 AN: 1760

Alfa AF: 0.0333 Hom.: 15

Bravo AF: 0.0300

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Aromatase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.37
DANN	Benign	0.73
PhyloP100		-0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	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: rs35636804; hg19: chr15-51500966;