8-143791725-T-G

Variant names:

• chr8-143791725-T-G
• NM_182706.5:c.4711A>C

Variant summary

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

The NM_182706.5(SCRIB):​c.4711A>C​(p.Lys1571Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,448,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCRIB NM_182706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14

Genes affected

SCRIB (HGNC:30377): (scribble planar cell polarity protein) This gene encodes a protein that was identified as being similar to the Drosophila scribble protein. The mammalian protein is involved in tumor suppression pathways. As a scaffold protein involved in cell polarization processes, this protein binds to many other proteins. The encoded protein binds to papillomavirus E6 protein via its PDZ domain and the C-terminus of E6. Two alternatively spliced transcript variants that encode different protein isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

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 rank	MANE	Protein	UniProt
SCRIB	NM_182706.5	c.4711A>C	p.Lys1571Gln	missense_variant	Exon 35 of 37	ENST00000356994.7	NP_874365.3
SCRIB	NM_015356.5	c.4695+151A>C		intron_variant	Intron 34 of 35		NP_056171.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCRIB	ENST00000356994.7	c.4711A>C	p.Lys1571Gln	missense_variant	Exon 35 of 37	2	NM_182706.5	ENSP00000349486.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448624 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 717702

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4711A>C (p.K1571Q) alteration is located in exon 35 (coding exon 35) of the SCRIB gene. This alteration results from a A to C substitution at nucleotide position 4711, causing the lysine (K) at amino acid position 1571 to be replaced by a glutamine (Q). 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
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.65	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.097
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Vest4		0.41
MutPred		0.25		Gain of ubiquitination at K1570 (P = 0.0301);
MVP		0.49
ClinPred		0.88	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -3

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: chr8-144873895;