11-65116546-C-G

Variant names:

• chr11-65116546-C-G
• rs755999355
• NM_014205.4:c.1108G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014205.4(ZNHIT2):​c.1108G>C​(p.Val370Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,800 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V370M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ZNHIT2 NM_014205.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055725813).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014205.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNHIT2	NM_014205.4	MANE Select	c.1108G>C	p.Val370Leu	missense	Exon 1 of 1	NP_055020.1	Q9UHR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNHIT2	ENST00000310597.6	TSL:6 MANE Select	c.1108G>C	p.Val370Leu	missense	Exon 1 of 1	ENSP00000308548.4	Q9UHR6
	ZNHIT2	ENST00000528598.1	TSL:3	c.*54G>C		downstream_gene	N/A	ENSP00000436896.1	E9PQB8
	TM7SF2	ENST00000529601.5	TSL:2	n.*1425C>G		downstream_gene	N/A	ENSP00000435458.1	E9PK81

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408800 Hom.: 0 Cov.: 71 AF XY: 0.00 AC XY: 0 AN XY: 693228

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32308

American (AMR) AF: 0.00 AC: 0 AN: 40038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23118

East Asian (EAS) AF: 0.00 AC: 0 AN: 38934

South Asian (SAS) AF: 0.00 AC: 0 AN: 79730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079462

Other (OTH) AF: 0.00 AC: 0 AN: 57954

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.8
DANN	Benign	0.73
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.13
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.012
Sift	Benign	0.33	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.25		Gain of disorder (P = 0.2321)
MVP		0.099
MPC		0.52
ClinPred		0.038	T
GERP RS		-1.1
Varity_R		0.040
gMVP		0.16
Mutation Taster		=96/4	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: rs755999355; hg19: chr11-64884018;