17-4744855-CCTCT-CCT

Variant names:

• chr17-4744855-CCT-C
• rs575052082
• NM_001136046.3:c.1838-10_1838-9delCT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BS1 BS2

The NM_001267822.1(ZMYND15):​c.1852_1853delCT​(p.Leu618ValfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,614,136 control chromosomes in the GnomAD database, including 50 homozygotes. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (46 hom.)
• Consequence: ZMYND15 NM_001267822.1 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.963
• Publications: 0 publications found

Genes affected

ZMYND15 (HGNC:20997): (zinc finger MYND-type containing 15) This gene encodes a MYND-containing zinc-binding protein with a nuclear localization sequence. A similar gene in mice has been shown to act as a testis-specific transcriptional repressor by recruiting histone deacetylase enzymes to regulate spatiotemporal expression of many haploid genes. This protein may play an important role in spermatogenesis. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jun 2012]

ZMYND15 Gene-Disease associations (from GenCC):

• spermatogenic failure 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 17-4744855-CCT-C is Benign according to our data. Variant chr17-4744855-CCT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 446037.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00251 (382/152278) while in subpopulation AMR AF = 0.0226 (345/15294). AF 95% confidence interval is 0.0206. There are 4 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267822.1. 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
	ZMYND15	NM_001136046.3	MANE Select	c.1838-10_1838-9delCT		intron	N/A	NP_001129518.1	Q9H091-1
	ZMYND15	NM_001267822.1		c.1852_1853delCT	p.Leu618ValfsTer5	frameshift	Exon 12 of 14	NP_001254751.1	Q9H091-3
	ZMYND15	NM_032265.2		c.1721-10_1721-9delCT		intron	N/A	NP_115641.1	Q9H091-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMYND15	ENST00000433935.6	TSL:2 MANE Select	c.1838-10_1838-9delCT		intron	N/A	ENSP00000391742.1	Q9H091-1
	ZMYND15	ENST00000592813.5	TSL:1	c.1721-10_1721-9delCT		intron	N/A	ENSP00000465435.1	Q9H091-2
	ZMYND15	ENST00000269289.10	TSL:5	c.1852_1853delCT	p.Leu618ValfsTer5	frameshift	Exon 12 of 14	ENSP00000269289.6	Q9H091-3

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152160 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00653 AC: 1642 AN: 251474 AF XY: 0.00475

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00137 AC: 2008 AN: 1461858 Hom.: 46 AF XY: 0.00112 AC XY: 813 AN XY: 727236

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.0425 AC: 1899 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111988

Other (OTH) AF: 0.00127 AC: 77 AN: 60396

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152278 Hom.: 4 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74446

African (AFR) AF: 0.000553 AC: 23 AN: 41556

American (AMR) AF: 0.0226 AC: 345 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00471

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=148/52	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 41

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

Other links and lift over

dbSNP: rs575052082; hg19: chr17-4648150;