11-65116566-C-G

Variant names:

• chr11-65116566-C-G
• NM_014205.4:c.1088G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014205.4(ZNHIT2):​c.1088G>C​(p.Arg363Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 34)
• Consequence: ZNHIT2 NM_014205.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.108

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

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=0.06161225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNHIT2	NM_014205.4	c.1088G>C	p.Arg363Thr	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.1088G>C	p.Arg363Thr	missense_variant	Exon 1 of 1	6	NM_014205.4	ENSP00000308548.4
ZNHIT2	ENST00000528598.1	c.*34G>C		downstream_gene_variant		3		ENSP00000436896.1
TM7SF2	ENST00000529601.5	n.*1445C>G		downstream_gene_variant		2		ENSP00000435458.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1088G>C (p.R363T) alteration is located in exon 1 (coding exon 1) of the ZNHIT2 gene. This alteration results from a G to C substitution at nucleotide position 1088, causing the arginine (R) at amino acid position 363 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.8
DANN	Benign	0.66
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.043
Sift	Benign	0.075	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.39		Loss of methylation at R363 (P = 0.0794);
MVP		0.099
MPC		0.75
ClinPred		0.026	T
GERP RS		-0.85
Varity_R		0.051
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64884038;