7-101223555-A-T

Position:

• chr7-101223555-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006349.3(ZNHIT1):​c.272A>T​(p.Gln91Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNHIT1 NM_006349.3 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.46

Genes affected

ZNHIT1 (HGNC:21688): (zinc finger HIT-type containing 1) Predicted to enable histone deacetylase binding activity and nucleosome binding activity. Predicted to be involved in histone exchange. Predicted to act upstream of or within several processes, including negative regulation of G0 to G1 transition; negative regulation of transcription by RNA polymerase II; and regulation of histone deacetylation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNHIT1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNHIT1	NM_006349.3	c.272A>T	p.Gln91Leu	missense_variant, splice_region_variant	3/5	ENST00000305105.3	NP_006340.1
ZNHIT1	XM_011515739.3	c.317A>T	p.Gln106Leu	missense_variant, splice_region_variant	3/5		XP_011514041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNHIT1	ENST00000305105.3	c.272A>T	p.Gln91Leu	missense_variant, splice_region_variant	3/5	1	NM_006349.3	ENSP00000304593.2
ZNHIT1	ENST00000485387.1	n.2473A>T		splice_region_variant, non_coding_transcript_exon_variant	2/4	1
ZNHIT1	ENST00000461205.5	n.469A>T		splice_region_variant, non_coding_transcript_exon_variant	4/5	3
ZNHIT1	ENST00000492315.5	n.3765A>T		splice_region_variant, non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The c.272A>T (p.Q91L) alteration is located in exon 3 (coding exon 3) of the ZNHIT1 gene. This alteration results from a A to T substitution at nucleotide position 272, causing the glutamine (Q) at amino acid position 91 to be replaced by a leucine (L). 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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.76	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.19
Sift	Uncertain	0.028	D
Sift4G	Benign	0.14	T
Polyphen		0.099	B
Vest4		0.47
MutPred		0.32		Loss of solvent accessibility (P = 0.0217);
MVP		0.22
MPC		0.42
ClinPred		0.92	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.24
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: 1

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: chr7-100866836;