chr1-85657892-C-T

Variant names:

• chr1-85657892-C-T
• NM_017953.4:c.1327G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017953.4(ZNHIT6):​c.1327G>A​(p.Val443Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,454,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZNHIT6 NM_017953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

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.1327G>A	p.Val443Met	missense	Exon 9 of 10	NP_060423.3
	ZNHIT6	NM_001170670.2		c.1210G>A	p.Val404Met	missense	Exon 10 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.1327G>A	p.Val443Met	missense	Exon 9 of 10	ENSP00000359606.3	Q9NWK9-1
	ZNHIT6	ENST00000879064.1		c.1396G>A	p.Val466Met	missense	Exon 10 of 11	ENSP00000549123.1
	ZNHIT6	ENST00000431532.6	TSL:2	c.1210G>A	p.Val404Met	missense	Exon 10 of 11	ENSP00000414344.2	Q9NWK9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454388 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723492

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.00 AC: 0 AN: 84736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1107702

Other (OTH) AF: 0.00 AC: 0 AN: 60128

GnomAD4 genome Cov.: 32

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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.52		Gain of disorder (P = 0.1008)
MVP		0.86
MPC		0.69
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.66
gMVP		0.63
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

hg19: chr1-86123575;