19-22757752-A-G

Variant names:

• chr19-22757752-A-G
• rs12980594
• NM_001080409.3:c.2157T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001080409.3(ZNF99):​c.2157T>C​(p.Thr719Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 120,558 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF99 NM_001080409.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.37
• Publications: 1 publications found

Genes affected

ZNF99 (HGNC:13175): (zinc finger protein 99) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.11).
• BP6: Variant 19-22757752-A-G is Benign according to our data. Variant chr19-22757752-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2649652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.37 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080409.3. 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
	ZNF99	NM_001080409.3	MANE Select	c.2157T>C	p.Thr719Thr	synonymous	Exon 4 of 4	NP_001073878.2	A8MXY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF99	ENST00000596209.4	TSL:5 MANE Select	c.2157T>C	p.Thr719Thr	synonymous	Exon 4 of 4	ENSP00000472969.1	A8MXY4

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 483 AN: 120460 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.00718

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.000682

Gnomad EAS AF: 0.00995

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00705

Gnomad MID AF: 0.0467

Gnomad NFE AF: 0.00211

Gnomad OTH AF: 0.00428

GnomAD2 exomes AF: 0.0000372 AC: 9 AN: 242200 AF XY: 0.0000454

Gnomad AFR exome AF: 0.0000694

Gnomad AMR exome AF: 0.0000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000488

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000165 AC: 24 AN: 1453610 Hom.: 1 Cov.: 42 AF XY: 0.0000221 AC XY: 16 AN XY: 723408

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

African (AFR) AF: 0.0000919 AC: 3 AN: 32634

American (AMR) AF: 0.0000226 AC: 1 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25806

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52560

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5694

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1107696

Other (OTH) AF: 0.000117 AC: 7 AN: 59722

⚠️ 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: 0.00401 AC: 483 AN: 120558 Hom.: 0 Cov.: 31 AF XY: 0.00389 AC XY: 231 AN XY: 59400

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

African (AFR) AF: 0.00628 AC: 194 AN: 30902

American (AMR) AF: 0.00255 AC: 32 AN: 12544

Ashkenazi Jewish (ASJ) AF: 0.000682 AC: 2 AN: 2934

East Asian (EAS) AF: 0.00947 AC: 37 AN: 3906

South Asian (SAS) AF: 0.00676 AC: 25 AN: 3698

European-Finnish (FIN) AF: 0.00705 AC: 55 AN: 7802

Middle Eastern (MID) AF: 0.0473 AC: 7 AN: 148

European-Non Finnish (NFE) AF: 0.00211 AC: 119 AN: 56270

Other (OTH) AF: 0.00422 AC: 7 AN: 1658

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0179 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000600

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.4
DANN	Benign	0.33
PhyloP100		-6.4

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: rs12980594; hg19: chr19-22940554; COSMIC: COSV68054657;