11-65116486-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.1168G>A​(p.Val390Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000705 in 1,518,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V390L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

ZNHIT2
NM_014205.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.80
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]
TM7SF2 (HGNC:11863): (transmembrane 7 superfamily member 2) Enables delta14-sterol reductase activity. Involved in cholesterol biosynthetic process. Located in endoplasmic reticulum. Part of receptor complex. [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=0.017843485).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNHIT2NM_014205.4 linkc.1168G>A p.Val390Met 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.1168G>A p.Val390Met missense_variant Exon 1 of 1 6 NM_014205.4 ENSP00000308548.4 Q9UHR6
ZNHIT2ENST00000528598.1 linkc.*114G>A downstream_gene_variant 3 ENSP00000436896.1 E9PQB8
TM7SF2ENST00000529292.5 linkn.*983C>T downstream_gene_variant 5 ENSP00000436370.1 E9PP79
TM7SF2ENST00000529601.5 linkn.*1365C>T downstream_gene_variant 2 ENSP00000435458.1 E9PK81

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152224
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000122
AC:
22
AN:
179752
Hom.:
0
AF XY:
0.000137
AC XY:
13
AN XY:
94662
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000911
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000259
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000186
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000710
AC:
97
AN:
1365878
Hom.:
0
Cov.:
70
AF XY:
0.0000942
AC XY:
63
AN XY:
668484
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000998
Gnomad4 ASJ exome
AF:
0.0000499
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000225
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000686
Gnomad4 OTH exome
AF:
0.0000535
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152224
Hom.:
0
Cov.:
34
AF XY:
0.0000403
AC XY:
3
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000768
Hom.:
0
Bravo
AF:
0.0000529
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000928
AC:
11

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 17, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1168G>A (p.V390M) 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 1168, causing the valine (V) at amino acid position 390 to be replaced by a methionine (M). 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
0.086
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
5.2
DANN
Benign
0.83
DEOGEN2
Benign
0.0095
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.54
T
M_CAP
Benign
0.0052
T
MetaRNN
Benign
0.018
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.29
N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
0.16
N
REVEL
Benign
0.0030
Sift
Benign
0.24
T
Sift4G
Benign
0.20
T
Polyphen
0.0030
B
Vest4
0.072
MutPred
0.18
Gain of disorder (P = 0.0711);
MVP
0.048
MPC
0.51
ClinPred
0.020
T
GERP RS
-6.8
Varity_R
0.029
gMVP
0.13

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

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

Other links and lift over

dbSNP: rs200656382; hg19: chr11-64883958; API