3-44568311-C-T

Variant names:

• chr3-44568311-C-T
• rs140086958
• NM_001288590.2:c.689C>T

Variant summary

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

The NM_001288590.2(ZKSCAN7):​c.689C>T​(p.Thr230Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,100 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ZKSCAN7 NM_001288590.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.214
• Publications: 0 publications found

Genes affected

ZKSCAN7 (HGNC:12955): (zinc finger with KRAB and SCAN domains 7) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZKSCAN7-AS1 (HGNC:53964): (ZKSCAN7 ZNF cluster antisense RNA 1)

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=0.05796951).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZKSCAN7	NM_001288590.2	c.689C>T	p.Thr230Ile	missense_variant	Exon 5 of 6	ENST00000426540.6	NP_001275519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZKSCAN7	ENST00000426540.6	c.689C>T	p.Thr230Ile	missense_variant	Exon 5 of 6	2	NM_001288590.2	ENSP00000395524.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249200 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1459956 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726188

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 85816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111240

Other (OTH) AF: 0.0000166 AC: 1 AN: 60312

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.689C>T (p.T230I) alteration is located in exon 5 (coding exon 4) of the ZKSCAN7 gene. This alteration results from a C to T substitution at nucleotide position 689, causing the threonine (T) at amino acid position 230 to be replaced by an isoleucine (I). 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	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.44
DANN	Benign	0.92
DEOGEN2	Benign	0.069	T;.;.;T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.091	N
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.058	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;L;L;L;.;.
PhyloP100		-0.21
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.68	N;N;N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.30	T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;D
Polyphen		0.089	B;B;B;B;.;.
Vest4		0.089
MVP		0.14
MPC		0.071
ClinPred		0.051	T
GERP RS		2.3
Varity_R		0.046
gMVP		0.046
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs140086958; hg19: chr3-44609803;