3-52423087-C-CCA

Variant names:

• chr3-52423087-C-CCA
• rs201539522
• NM_016483.7:c.920-3_920-2dupCA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PVS1_Strong BP6_Moderate BS1 BS2

The NM_016483.7(PHF7):​c.920-3_920-2dupCA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,600,238 control chromosomes in the GnomAD database, including 71 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (67 hom.)
• Consequence: PHF7 NM_016483.7 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0690

Genes affected

PHF7 (HGNC:18458): (PHD finger protein 7) Spermatogenesis is a complex process regulated by extracellular and intracellular factors as well as cellular interactions among interstitial cells of the testis, Sertoli cells, and germ cells. This gene is expressed in the testis in Sertoli cells but not germ cells. The protein encoded by this gene contains plant homeodomain (PHD) finger domains, also known as leukemia associated protein (LAP) domains, believed to be involved in transcriptional regulation. The protein, which localizes to the nucleus of transfected cells, has been implicated in the transcriptional regulation of spermatogenesis. Alternate splicing results in multiple transcript variants of this gene. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.4808028 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: ctgcctttctctcaccacAGact. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 3-52423087-C-CCA is Benign according to our data. Variant chr3-52423087-C-CCA is described in ClinVar as [Benign]. Clinvar id is 776465.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00385 (587/152316) while in subpopulation SAS AF= 0.0234 (113/4832). AF 95% confidence interval is 0.0199. There are 4 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF7	NM_016483.7	c.920-3_920-2dupCA		splice_acceptor_variant, intron_variant	Intron 10 of 10	ENST00000327906.8	NP_057567.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF7	ENST00000327906.8	c.920-4_920-3insCA		splice_region_variant, intron_variant	Intron 10 of 10	1	NM_016483.7	ENSP00000333024.3

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 588 AN: 152198 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00750

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00594 AC: 1491 AN: 250958 Hom.: 11 AF XY: 0.00697 AC XY: 946 AN XY: 135634

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00772

Gnomad SAS exome AF: 0.0232

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00419

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00587 AC: 8495 AN: 1447922 Hom.: 67 Cov.: 28 AF XY: 0.00639 AC XY: 4607 AN XY: 721248

Gnomad4 AFR exome AF: 0.000573

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.00162

Gnomad4 EAS exome AF: 0.00780

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00506

Gnomad4 OTH exome AF: 0.00556

GnomAD4 genome AF: 0.00385 AC: 587 AN: 152316 Hom.: 4 Cov.: 32 AF XY: 0.00401 AC XY: 299 AN XY: 74494

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00751

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00473

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00426 Hom.: 2

Bravo AF: 0.00307

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00498

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

PHF7-related disorder Benign:1

Apr 13, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Dec 29, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201539522; hg19: chr3-52457103;