11-3360016-T-C

Variant names:

• chr11-3360016-T-C
• rs776095965
• NM_001130520.3:c.992A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001130520.3(ZNF195):​c.992A>G​(p.Glu331Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF195 NM_001130520.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

Genes affected

ZNF195 (HGNC:12986): (zinc finger protein 195) This gene encodes a protein belonging to the Krueppel C2H2-type zinc-finger protein family. These family members are transcription factors that are implicated in a variety of cellular processes. This gene is located near the centromeric border of chromosome 11p15.5, next to an imprinted domain that is associated with maternal-specific loss of heterozygosity in Wilms' tumors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27751985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF195	NM_001130520.3	c.992A>G	p.Glu331Gly	missense_variant	Exon 6 of 6	ENST00000399602.9	NP_001123992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF195	ENST00000399602.9	c.992A>G	p.Glu331Gly	missense_variant	Exon 6 of 6	1	NM_001130520.3	ENSP00000382511.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249210 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135220

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.992A>G (p.E331G) alteration is located in exon 6 (coding exon 6) of the ZNF195 gene. This alteration results from a A to G substitution at nucleotide position 992, causing the glutamic acid (E) at amino acid position 331 to be replaced by a glycine (G). 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	0.35
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;T;T;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.00030	N
LIST_S2	Benign	0.44	T;T;T;T;.;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.;.
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-5.6	D;D;.;D;D;D;D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;.;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D
Polyphen		0.97	D;P;.;D;P;D;P
Vest4		0.13
MutPred		0.54		.;.;.;Loss of stability (P = 0.0481);.;.;.;
MVP		0.66
MPC		0.85
ClinPred		0.98	D
GERP RS		0.50
Varity_R		0.31
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs776095965; hg19: chr11-3381246;