rs121434538

chr15-51222349-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_000103.4(CYP19A1):c.628G>A(p.Glu210Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CYP19A1 NM_000103.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.56

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 Likely_pathogenic. Variant got 6 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-51222349-C-T is Pathogenic according to our data. Variant chr15-51222349-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17826.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-51222349-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP19A1	NM_000103.4	c.628G>A	p.Glu210Lys	missense_variant, splice_region_variant	5/10	ENST00000396402.6
MIR4713HG	NR_146310.1	n.195-55634C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP19A1	ENST00000396402.6	c.628G>A	p.Glu210Lys	missense_variant, splice_region_variant	5/10	1	NM_000103.4	P1
MIR4713HG	ENST00000559909.1	n.195-55634C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251154 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Aromatase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 14, 2023

Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 17826). This variant is also known as c.655G>A. This missense change has been observed in individuals with CYP19A1-related conditions (PMID: 14602738, 25301327, 25415177, 27693882). This variant is present in population databases (rs121434538, gnomAD 0.006%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 210 of the CYP19A1 protein (p.Glu210Lys). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	56
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;D;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.0	M;M;M;.;.
MutationTaster	Benign	0.90	A;A;A;A;A;A
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.78
MutPred		0.81		Gain of ubiquitination at E210 (P = 0.0177);Gain of ubiquitination at E210 (P = 0.0177);Gain of ubiquitination at E210 (P = 0.0177);Gain of ubiquitination at E210 (P = 0.0177);Gain of ubiquitination at E210 (P = 0.0177);
MVP		0.86
MPC		0.61
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.72
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.83		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121434538; hg19: chr15-51514546;