chr19-9295771-C-T

Variant names:

• chr19-9295771-C-T
• rs565224634
• NM_198535.3:c.1633G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198535.3(ZNF699):​c.1633G>A​(p.Ala545Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,603,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF699 NM_198535.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.35
• Publications: 0 publications found

Genes affected

ZNF699 (HGNC:24750): (zinc finger protein 699) Predicted to enable DNA-binding transcription factor 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]

ZNF699 Gene-Disease associations (from GenCC):

• DEGCAGS syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049102277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF699	NM_198535.3	c.1633G>A	p.Ala545Thr	missense_variant	Exon 6 of 6	ENST00000591998.6	NP_940937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF699	ENST00000591998.6	c.1633G>A	p.Ala545Thr	missense_variant	Exon 6 of 6	5	NM_198535.3	ENSP00000467723.1
ZNF699	ENST00000308650.4	c.1633G>A	p.Ala545Thr	missense_variant	Exon 5 of 5	1		ENSP00000311596.3

Frequencies

GnomAD3 genomes AF: 0.00000703 AC: 1 AN: 142230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250318 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461574 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727076

⚠️ 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: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44672

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000702 AC: 1 AN: 142368 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 69560

African (AFR) AF: 0.00 AC: 0 AN: 38102

American (AMR) AF: 0.00 AC: 0 AN: 14304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3356

East Asian (EAS) AF: 0.00 AC: 0 AN: 4664

South Asian (SAS) AF: 0.00 AC: 0 AN: 4388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 64894

Other (OTH) AF: 0.00 AC: 0 AN: 1944

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1633G>A (p.A545T) alteration is located in exon 5 (coding exon 5) of the ZNF699 gene. This alteration results from a G to A substitution at nucleotide position 1633, causing the alanine (A) at amino acid position 545 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.13	N;N
PhyloP100		-1.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.0	.;N
REVEL	Benign	0.035
Sift	Benign	0.37	.;T
Sift4G	Benign	0.33	T;T
Polyphen		0.32	B;B
Vest4		0.14
MutPred		0.29		Gain of disorder (P = 0.0988);Gain of disorder (P = 0.0988);
MVP		0.24
MPC		0.44
ClinPred		0.49	T
GERP RS		-0.096
Varity_R		0.059
gMVP		0.021
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs565224634; hg19: chr19-9406447;