19-56190079-C-A

Variant names:

• chr19-56190079-C-A
• rs771771953
• NM_001080456.5:c.1236G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080456.5(ZSCAN5B):​c.1236G>T​(p.Met412Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. M412L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZSCAN5B NM_001080456.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.77

Genes affected

ZSCAN5B (HGNC:34246): (zinc finger and SCAN domain containing 5B) 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018455863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSCAN5B	NM_001080456.5	c.1236G>T	p.Met412Ile	missense_variant	Exon 5 of 5	ENST00000586855.7	NP_001073925.2
ZSCAN5B	NM_001385638.1	c.1236G>T	p.Met412Ile	missense_variant	Exon 5 of 5		NP_001372567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSCAN5B	ENST00000586855.7	c.1236G>T	p.Met412Ile	missense_variant	Exon 5 of 5	5	NM_001080456.5	ENSP00000466072.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249878 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000329

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000495 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1236G>T (p.M412I) alteration is located in exon 4 (coding exon 4) of the ZSCAN5B gene. This alteration results from a G to T substitution at nucleotide position 1236, causing the methionine (M) at amino acid position 412 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.22
DANN	Benign	0.68
DEOGEN2	Benign	0.0052	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.43	.;T
M_CAP	Benign	0.00061	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.76	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.010
Sift	Benign	0.10	.;T
Sift4G	Benign	0.11	T;T
Polyphen		0.025	B;B
Vest4		0.10
MutPred		0.33		Loss of disorder (P = 0.0655);Loss of disorder (P = 0.0655);
MVP		0.12
MPC		0.014
ClinPred		0.026	T
GERP RS		-6.3
Varity_R		0.077
gMVP		0.042

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

Publications

LitVar

Other links and lift over

dbSNP: rs771771953; hg19: chr19-56701448;