chr19-47544921-C-T

Variant names:

• chr19-47544921-C-T
• rs386834267
• NM_001277075.3:c.1608G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001277075.3(ZNF541):​c.1608G>A​(p.Pro536Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ZNF541 NM_001277075.3 synonymous
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -5.88
• Publications: 0 publications found

Genes affected

ZNF541 (HGNC:25294): (zinc finger protein 541) Predicted to enable transcription corepressor activity. Predicted to be involved in histone deacetylation; negative regulation of transcription, DNA-templated; and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of histone deacetylase complex and transcription regulator complex. [provided by Alliance of Genome Resources, Apr 2022]

ZNF541 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: LIMITED Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.015).
• BP7: Synonymous conserved (PhyloP=-5.88 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277075.3. 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
	ZNF541	NM_001277075.3	MANE Select	c.1608G>A	p.Pro536Pro	synonymous	Exon 5 of 17	NP_001264004.1	Q9H0D2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF541	ENST00000391901.8	TSL:5 MANE Select	c.1608G>A	p.Pro536Pro	synonymous	Exon 5 of 17	ENSP00000375770.3	Q9H0D2-3
	ZNF541	ENST00000595558.1	TSL:1	c.339G>A	p.Pro113Pro	synonymous	Exon 1 of 12	ENSP00000471665.1	M0R167
	ZNF541	ENST00000263351.9	TSL:1	c.378G>A	p.Pro126Pro	synonymous	Exon 1 of 7	ENSP00000263351.5	H7BXG6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383566 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 682690

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

African (AFR) AF: 0.00 AC: 0 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078764

Other (OTH) AF: 0.00 AC: 0 AN: 57896

⚠️ 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 Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.072
DANN	Benign	0.60
PhyloP100		-5.9
PromoterAI		-0.0027	Neutral

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: rs386834267; hg19: chr19-48048178;