11-3360561-C-A

Variant names:

• chr11-3360561-C-A
• rs371842951
• NM_001130520.3:c.447G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001130520.3(ZNF195):​c.447G>T​(p.Met149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF195 NM_001130520.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.44
• Publications: 0 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.079876065).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130520.3. 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
	ZNF195	NM_001130520.3	MANE Select	c.447G>T	p.Met149Ile	missense	Exon 6 of 6	NP_001123992.1	O14628-1
	ZNF195	NM_001242841.2		c.390G>T	p.Met130Ile	missense	Exon 6 of 6	NP_001229770.1	O14628-6
	ZNF195	NM_001130519.3		c.378G>T	p.Met126Ile	missense	Exon 5 of 5	NP_001123991.1	O14628-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF195	ENST00000399602.9	TSL:1 MANE Select	c.447G>T	p.Met149Ile	missense	Exon 6 of 6	ENSP00000382511.4	O14628-1
	ZNF195	ENST00000005082.13	TSL:1	c.378G>T	p.Met126Ile	missense	Exon 5 of 5	ENSP00000005082.9	O14628-5
	ZNF195	ENST00000354599.10	TSL:1	c.231G>T	p.Met77Ile	missense	Exon 4 of 4	ENSP00000346613.6	O14628-4

Frequencies

GnomAD3 genomes AF: 0.000193 AC: 25 AN: 129844 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.000288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000790 AC: 15 AN: 189772 AF XY: 0.0000672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000711

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000237

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000617 AC: 85 AN: 1376760 Hom.: 0 Cov.: 32 AF XY: 0.0000677 AC XY: 46 AN XY: 679756

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

African (AFR) AF: 0.000135 AC: 4 AN: 29610

American (AMR) AF: 0.0000328 AC: 1 AN: 30452

Ashkenazi Jewish (ASJ) AF: 0.0000881 AC: 2 AN: 22700

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37880

South Asian (SAS) AF: 0.00 AC: 0 AN: 73210

European-Finnish (FIN) AF: 0.0000401 AC: 2 AN: 49824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5260

European-Non Finnish (NFE) AF: 0.0000672 AC: 72 AN: 1071538

Other (OTH) AF: 0.0000533 AC: 3 AN: 56286

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000208 AC: 27 AN: 129938 Hom.: 0 Cov.: 28 AF XY: 0.000242 AC XY: 15 AN XY: 61870

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

African (AFR) AF: 0.000263 AC: 9 AN: 34172

American (AMR) AF: 0.000162 AC: 2 AN: 12356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3160

East Asian (EAS) AF: 0.00 AC: 0 AN: 4548

South Asian (SAS) AF: 0.000740 AC: 3 AN: 4056

European-Finnish (FIN) AF: 0.000288 AC: 2 AN: 6938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.000178 AC: 11 AN: 61846

Other (OTH) AF: 0.00 AC: 0 AN: 1754

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000808318), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000214 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.40
DANN	Benign	0.43
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00046	N
LIST_S2	Benign	0.0029	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.68	N
PhyloP100		-1.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.047
Sift	Benign	0.72	T
Sift4G	Benign	0.70	T
Polyphen		0.39	B
Vest4		0.16
MutPred		0.57		Gain of catalytic residue at M149 (P = 0.0089)
MVP		0.59
MPC		0.25
ClinPred		0.0052	T
GERP RS		-0.54
Varity_R		0.038
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: rs371842951; hg19: chr11-3381791;