11-65116486-C-T

Variant names:

• chr11-65116486-C-T
• rs200656382
• NM_014205.4:c.1168G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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. 16/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.80
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017843485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNHIT2	NM_014205.4	c.1168G>A	p.Val390Met	missense_variant	Exon 1 of 1	ENST00000310597.6	NP_055020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNHIT2	ENST00000310597.6	c.1168G>A	p.Val390Met	missense_variant	Exon 1 of 1	6	NM_014205.4	ENSP00000308548.4
ZNHIT2	ENST00000528598.1	c.*114G>A		downstream_gene_variant		3		ENSP00000436896.1
TM7SF2	ENST00000529292.5	n.*983C>T		downstream_gene_variant		5		ENSP00000436370.1
TM7SF2	ENST00000529601.5	n.*1365C>T		downstream_gene_variant		2		ENSP00000435458.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 34

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

GnomAD2 exomes AF: 0.000122 AC: 22 AN: 179752 AF XY: 0.000137

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 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

African (AFR) AF: 0.00 AC: 0 AN: 30358

American (AMR) AF: 0.0000998 AC: 3 AN: 30062

Ashkenazi Jewish (ASJ) AF: 0.0000499 AC: 1 AN: 20034

East Asian (EAS) AF: 0.00 AC: 0 AN: 38696

South Asian (SAS) AF: 0.000225 AC: 16 AN: 71268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49868

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5302

European-Non Finnish (NFE) AF: 0.0000686 AC: 73 AN: 1064202

Other (OTH) AF: 0.0000535 AC: 3 AN: 56088

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

African (AFR) AF: 0.0000241 AC: 1 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

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

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
PhyloP100		-1.8
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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs200656382; hg19: chr11-64883958;