11-65116834-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014205.4(ZNHIT2):​c.820G>A​(p.Gly274Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000622 in 1,608,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

ZNHIT2
NM_014205.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48
Variant links:
Genes affected
ZNHIT2 (HGNC:1177): (zinc finger HIT-type containing 2) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.012243956).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNHIT2NM_014205.4 linkc.820G>A p.Gly274Ser missense_variant Exon 1 of 1 ENST00000310597.6 NP_055020.1 Q9UHR6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNHIT2ENST00000310597.6 linkc.820G>A p.Gly274Ser missense_variant Exon 1 of 1 6 NM_014205.4 ENSP00000308548.4 Q9UHR6
ZNHIT2ENST00000528598.1 linkc.325G>A p.Gly109Ser missense_variant Exon 2 of 2 3 ENSP00000436896.1 E9PQB8

Frequencies

GnomAD3 genomes
AF:
0.000289
AC:
44
AN:
152248
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00104
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000631
AC:
15
AN:
237690
Hom.:
0
AF XY:
0.0000765
AC XY:
10
AN XY:
130672
show subpopulations
Gnomad AFR exome
AF:
0.000920
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000329
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000385
AC:
56
AN:
1455764
Hom.:
0
Cov.:
34
AF XY:
0.0000414
AC XY:
30
AN XY:
724144
show subpopulations
Gnomad4 AFR exome
AF:
0.00132
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000289
AC:
44
AN:
152366
Hom.:
0
Cov.:
34
AF XY:
0.000309
AC XY:
23
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.00103
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000217
Hom.:
0
Bravo
AF:
0.000204
ESP6500AA
AF:
0.000457
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000745
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 22, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.820G>A (p.G274S) alteration is located in exon 1 (coding exon 1) of the ZNHIT2 gene. This alteration results from a G to A substitution at nucleotide position 820, causing the glycine (G) at amino acid position 274 to be replaced by a serine (S). 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
Benign
0.11
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.018
T;T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.56
FATHMM_MKL
Benign
0.054
N
LIST_S2
Benign
0.59
T;T
M_CAP
Benign
0.0077
T
MetaRNN
Benign
0.012
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
0.30
N;N
REVEL
Benign
0.015
Sift
Benign
0.70
T;T
Sift4G
Pathogenic
0.0
D;.
Polyphen
0.11
B;.
Vest4
0.21
MVP
0.072
MPC
1.4
ClinPred
0.088
T
GERP RS
3.8
Varity_R
0.10
gMVP
0.32

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375144201; hg19: chr11-64884306; API