1-212791726-G-T

Position:

• chr1-212791726-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015471.4(NSL1):​c.38C>A​(p.Pro13Gln) 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 1,461,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P13P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NSL1 NM_015471.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.259

Genes affected

NSL1 (HGNC:24548): (NSL1 component of MIS12 kinetochore complex) This gene encodes a protein with two coiled-coil domains that localizes to kinetochores, which are chromosome-associated structures that attach to microtubules and mediate chromosome movements during cell division. The encoded protein is part of a conserved protein complex that includes two chromodomain-containing proteins and a component of the outer plate of the kinetochore. This protein complex is proposed to bridge centromeric heterochromatin with the outer kinetochore structure. Multiple transcript variants encoding different isoforms have been found for this gene. There is a pseudogene of the 3' UTR region of this gene on chromosome X. [provided by RefSeq, Jul 2014]

NSL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10892764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSL1	NM_015471.4	c.38C>A	p.Pro13Gln	missense_variant	1/6	ENST00000366977.8	NP_056286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSL1	ENST00000366977.8	c.38C>A	p.Pro13Gln	missense_variant	1/6	1	NM_015471.4	ENSP00000355944.3
NSL1	ENST00000626725.1	c.38C>A	p.Pro13Gln	missense_variant	1/7	2		ENSP00000486783.1
NSL1	ENST00000366976.3	c.38C>A	p.Pro13Gln	missense_variant	1/5	2		ENSP00000355943.1
NSL1	ENST00000487995.1	n.57C>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461162 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726854

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Sep 22, 2022

The c.38C>A (p.P13Q) alteration is located in exon 1 (coding exon 1) of the NSL1 gene. This alteration results from a C to A substitution at nucleotide position 38, causing the proline (P) at amino acid position 13 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
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.3
DANN	Benign	0.90
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.058
Sift	Benign	0.053	T;D;.
Sift4G	Benign	0.45	T;T;D
Polyphen		0.43	B;.;.
Vest4		0.30
MutPred		0.29		Loss of catalytic residue at P12 (P = 0.0252);Loss of catalytic residue at P12 (P = 0.0252);Loss of catalytic residue at P12 (P = 0.0252);
MVP		0.41
MPC		0.23
ClinPred		0.19	T
GERP RS		-0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.028
gMVP		0.34

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: rs897178793; hg19: chr1-212965068;