Genetic Variant NHSL3:p.Pro6Ser (chr1-32741970-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020888.3(NHSL3):c.16C>T(p.Pro6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000711 in 1,124,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

NHSL3
NM_020888.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.189

Variant links:

Genes affected

NHSL3 (HGNC:29301): (NHS like 3) Predicted to be involved in cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

NHSL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.06199798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL3	NM_020888.3 link	c.16C>T	p.Pro6Ser	missense_variant	Exon 1 of 7	ENST00000401073.7	NP_065939.2	Q9P206-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA1522	ENST00000401073.7 link	c.16C>T	p.Pro6Ser	missense_variant	Exon 1 of 7	2	NM_020888.3	ENSP00000383851.2		Q9P206-2

Frequencies

GnomAD3 genomes

AF:

0.00000675

AC:

AN:

148148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000717

AC:

AN:

976312

Hom.:

Cov.:

AF XY:

0.00000652

AC XY:

AN XY:

460244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000510

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000523

Gnomad4 SAS exome

AF:

0.0000544

Gnomad4 FIN exome

AF:

0.0000594

Gnomad4 NFE exome

AF:

0.00000118

Gnomad4 OTH exome

AF:

0.0000542

GnomAD4 genome

AF:

0.00000675

AC:

AN:

148242

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000199

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16C>T (p.P6S) alteration is located in exon 1 (coding exon 1) of the KIAA1522 gene. This alteration results from a C to T substitution at nucleotide position 16, causing the proline (P) at amino acid position 6 to be replaced by a serine (S). 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

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.33

M_CAP

Benign

0.050

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.97

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.62

REVEL

Benign

0.027

Sift

Pathogenic

0.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.20

MutPred

0.26

Gain of phosphorylation at P6 (P = 0.0022);

MVP

0.068

MPC

0.12

ClinPred

0.84

GERP RS

0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over