rs765256116

Variant names:

• chr1-85677296-C-T
• rs765256116
• NM_017953.4:c.1187G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017953.4(ZNHIT6):​c.1187G>A​(p.Arg396His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000667 in 1,605,098 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R396C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: ZNHIT6 NM_017953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.617
• Publications: 1 publications found

Genes affected

ZNHIT6 (HGNC:26089): (zinc finger HIT-type containing 6) Enables ATPase binding activity; TFIID-class transcription factor complex binding activity; and identical protein binding activity. Involved in box C/D snoRNP assembly; protein complex oligomerization; and snoRNA localization. Located in extracellular exosome. Part of pre-snoRNP complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01689437).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017953.4. 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
	ZNHIT6	NM_017953.4	MANE Select	c.1187G>A	p.Arg396His	missense	Exon 8 of 10	NP_060423.3
	ZNHIT6	NM_001170670.2		c.1070G>A	p.Arg357His	missense	Exon 9 of 11	NP_001164141.1	Q9NWK9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNHIT6	ENST00000370574.4	TSL:1 MANE Select	c.1187G>A	p.Arg396His	missense	Exon 8 of 10	ENSP00000359606.3	Q9NWK9-1
	ZNHIT6	ENST00000879064.1		c.1256G>A	p.Arg419His	missense	Exon 9 of 11	ENSP00000549123.1
	ZNHIT6	ENST00000431532.6	TSL:2	c.1070G>A	p.Arg357His	missense	Exon 9 of 11	ENSP00000414344.2	Q9NWK9-2

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151920 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 33 AN: 243990 AF XY: 0.000114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000389

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.0000372 AC: 54 AN: 1453178 Hom.: 0 Cov.: 30 AF XY: 0.0000360 AC XY: 26 AN XY: 722624

African (AFR) AF: 0.00 AC: 0 AN: 33084

American (AMR) AF: 0.000421 AC: 18 AN: 42800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.000279 AC: 11 AN: 39410

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1109328

Other (OTH) AF: 0.0000666 AC: 4 AN: 60022

GnomAD4 genome AF: 0.000349 AC: 53 AN: 151920 Hom.: 2 Cov.: 33 AF XY: 0.000458 AC XY: 34 AN XY: 74198

African (AFR) AF: 0.0000242 AC: 1 AN: 41350

American (AMR) AF: 0.00335 AC: 51 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67982

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

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000253

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.62
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.049
Sift	Benign	0.26	T
Sift4G	Benign	0.64	T
Polyphen		0.0080	B
Vest4		0.072
MutPred		0.42		Loss of MoRF binding (P = 0.0144)
MVP		0.18
MPC		0.21
ClinPred		0.053	T
GERP RS		-1.3
Varity_R		0.025
gMVP		0.13
Mutation Taster		=93/7	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: rs765256116; hg19: chr1-86142979; COSMIC: COSV65326659;