11-65116546-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.1108G>A​(p.Val370Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,561,076 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

ZNHIT2
NM_014205.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.126
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=0.033153564).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNHIT2NM_014205.4 linkc.1108G>A p.Val370Met 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.1108G>A p.Val370Met missense_variant Exon 1 of 1 6 NM_014205.4 ENSP00000308548.4 Q9UHR6
ZNHIT2ENST00000528598.1 linkc.*54G>A downstream_gene_variant 3 ENSP00000436896.1 E9PQB8
TM7SF2ENST00000529601.5 linkn.*1425C>T downstream_gene_variant 2 ENSP00000435458.1 E9PK81

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152276
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000272
AC:
6
AN:
220560
Hom.:
0
AF XY:
0.0000254
AC XY:
3
AN XY:
118102
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000570
Gnomad EAS exome
AF:
0.0000560
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000100
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000994
AC:
14
AN:
1408800
Hom.:
0
Cov.:
71
AF XY:
0.0000101
AC XY:
7
AN XY:
693228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000346
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000463
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152276
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74390
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1108G>A (p.V370M) 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 1108, causing the valine (V) at amino acid position 370 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
0.092
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
11
DANN
Benign
0.87
DEOGEN2
Benign
0.013
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.043
N
LIST_S2
Benign
0.57
T
M_CAP
Benign
0.0083
T
MetaRNN
Benign
0.033
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.1
L
PrimateAI
Benign
0.47
T
PROVEAN
Benign
0.010
N
REVEL
Benign
0.014
Sift
Benign
0.24
T
Sift4G
Uncertain
0.060
T
Polyphen
0.0030
B
Vest4
0.11
MutPred
0.37
Gain of catalytic residue at V370 (P = 0.0807);
MVP
0.10
MPC
0.81
ClinPred
0.0096
T
GERP RS
-1.1
Varity_R
0.028
gMVP
0.13

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: rs755999355; hg19: chr11-64884018; API