1-52813521-CTTTT-CTTTTT

Variant names:

• chr1-52813521-C-CT
• rs760756606
• NM_024646.3:c.1696-5dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_024646.3(ZYG11B):​c.1696-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,314,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (0 hom.)
• Consequence: ZYG11B NM_024646.3 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.460
• Publications: 0 publications found

Genes affected

ZYG11B (HGNC:25820): (zyg-11 family member B, cell cycle regulator) Involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process and protein quality control for misfolded or incompletely synthesized proteins. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ZYG11B Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 1-52813521-C-CT is Benign according to our data. Variant chr1-52813521-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 3060468.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 114 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024646.3. 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
	ZYG11B	NM_024646.3	MANE Select	c.1696-5dupT		splice_region intron	N/A	NP_078922.1	Q9C0D3-1
	ZYG11B	NM_001441954.1		c.1684-5dupT		splice_region intron	N/A	NP_001428883.1
	ZYG11B	NR_199864.1		n.2040-5dupT		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZYG11B	ENST00000294353.7	TSL:1 MANE Select	c.1696-15_1696-14insT		intron	N/A	ENSP00000294353.6	Q9C0D3-1
	ZYG11B	ENST00000884648.1		c.1693-15_1693-14insT		intron	N/A	ENSP00000554707.1
	ZYG11B	ENST00000959293.1		c.1645-15_1645-14insT		intron	N/A	ENSP00000629352.1

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 114 AN: 149546 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.000298

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.0155 AC: 1540 AN: 99270 AF XY: 0.0143

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.0134

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.00966 AC: 11260 AN: 1165094 Hom.: 0 Cov.: 27 AF XY: 0.00921 AC XY: 5330 AN XY: 578788

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0121 AC: 306 AN: 25344

American (AMR) AF: 0.00893 AC: 302 AN: 33830

Ashkenazi Jewish (ASJ) AF: 0.00795 AC: 160 AN: 20118

East Asian (EAS) AF: 0.00718 AC: 214 AN: 29804

South Asian (SAS) AF: 0.00859 AC: 569 AN: 66228

European-Finnish (FIN) AF: 0.00684 AC: 288 AN: 42110

Middle Eastern (MID) AF: 0.00652 AC: 31 AN: 4754

European-Non Finnish (NFE) AF: 0.0100 AC: 8956 AN: 895452

Other (OTH) AF: 0.00915 AC: 434 AN: 47454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000762 AC: 114 AN: 149642 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 48 AN XY: 72986

African (AFR) AF: 0.00233 AC: 95 AN: 40838

American (AMR) AF: 0.000268 AC: 4 AN: 14930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4710

European-Finnish (FIN) AF: 0.000298 AC: 3 AN: 10058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67270

Other (OTH) AF: 0.00146 AC: 3 AN: 2058

Alfa AF: 0.0305 Hom.: 0

Bravo AF: 0.000771

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ZYG11B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
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: rs760756606; hg19: chr1-53279193; COSMIC: COSV53749616;