rs8112524

Variant names:

• chr19-2250529-G-A
• rs8112524
• NM_000479.5:c.555+50G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-2250529-G-A
• chr19-2250529-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000479.5(AMH):​c.555+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 1,540,218 control chromosomes in the GnomAD database, including 263,320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21429 hom., cov: 33)
  • Exomes 𝑓: 0.59 (241891 hom.)
• Consequence: AMH NM_000479.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0860
• Publications: 11 publications found

Genes affected

AMH (HGNC:464): (anti-Mullerian hormone) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate N- and C-terminal cleavage products that homodimerize and associate to form a biologically active noncovalent complex. This complex binds to the anti-Mullerian hormone receptor type 2 and causes the regression of Mullerian ducts in the male embryo that would otherwise differentiate into the uterus and fallopian tubes. This protein also plays a role in Leydig cell differentiation and function and follicular development in adult females. Mutations in this gene result in persistent Mullerian duct syndrome. [provided by RefSeq, Jul 2016]

MIR4321 (HGNC:38244): (microRNA 4321) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-2250529-G-A is Benign according to our data. Variant chr19-2250529-G-A is described in ClinVar as Benign. ClinVar VariationId is 1262695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMH	NM_000479.5	c.555+50G>A		intron_variant	Intron 2 of 4	ENST00000221496.5	NP_000470.3
MIR4321	NR_036207.1	n.-110G>A		upstream_gene_variant
MIR4321	unassigned_transcript_3189	n.-159G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMH	ENST00000221496.5	c.555+50G>A		intron_variant	Intron 2 of 4	1	NM_000479.5	ENSP00000221496.2
AMH	ENST00000589313.2	n.786G>A		non_coding_transcript_exon_variant	Exon 1 of 3	5
AMH	ENST00000592877.1	n.437-123G>A		intron_variant	Intron 1 of 1	3
MIR4321	ENST00000592276.1	n.-110G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78486 AN: 151900 Hom.: 21440 Cov.: 33

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.701

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.551

GnomAD2 exomes AF: 0.534 AC: 77166 AN: 144390 AF XY: 0.539

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.623

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.607

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.587 AC: 814215 AN: 1388200 Hom.: 241891 Cov.: 50 AF XY: 0.585 AC XY: 400179 AN XY: 684476

African (AFR) AF: 0.339 AC: 10688 AN: 31492

American (AMR) AF: 0.495 AC: 17663 AN: 35674

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 15811 AN: 25122

East Asian (EAS) AF: 0.421 AC: 15020 AN: 35642

South Asian (SAS) AF: 0.511 AC: 40451 AN: 79092

European-Finnish (FIN) AF: 0.531 AC: 22527 AN: 42448

Middle Eastern (MID) AF: 0.626 AC: 2590 AN: 4138

European-Non Finnish (NFE) AF: 0.610 AC: 656605 AN: 1076962

Other (OTH) AF: 0.570 AC: 32860 AN: 57630

GnomAD4 genome AF: 0.516 AC: 78488 AN: 152018 Hom.: 21429 Cov.: 33 AF XY: 0.513 AC XY: 38159 AN XY: 74318

African (AFR) AF: 0.352 AC: 14606 AN: 41462

American (AMR) AF: 0.555 AC: 8478 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2213 AN: 3470

East Asian (EAS) AF: 0.409 AC: 2109 AN: 5158

South Asian (SAS) AF: 0.502 AC: 2422 AN: 4820

European-Finnish (FIN) AF: 0.519 AC: 5502 AN: 10596

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41191 AN: 67920

Other (OTH) AF: 0.547 AC: 1150 AN: 2104

Alfa AF: 0.577 Hom.: 34812

Bravo AF: 0.510

Asia WGS AF: 0.388 AC: 1353 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.9
DANN	Benign	0.90
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8112524; hg19: chr19-2250528; COSMIC: COSV55556302; COSMIC: COSV55556302;