2-230361622-G-T

Position:

• chr2-230361622-G-T

Variant summary

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

The NM_138402.6(SP140L):​c.448G>T​(p.Asp150Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,406,372 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: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SP140L NM_138402.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.88

Genes affected

SP140L (HGNC:25105): (SP140 nuclear body protein like) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nuclear body. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SP140L (HGNC:):

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/exons	MANE	Protein	UniProt
SP140L	NM_138402.6	c.448G>T	p.Asp150Tyr	missense_variant	5/19	ENST00000415673.7	NP_612411.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SP140L	ENST00000415673.7	c.448G>T	p.Asp150Tyr	missense_variant	5/19	5	NM_138402.6	ENSP00000397911.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1406372 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 2 AN XY: 694308

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: 0.00000370

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000302

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 06, 2022

The c.448G>T (p.D150Y) alteration is located in exon 5 (coding exon 5) of the SP140L gene. This alteration results from a G to T substitution at nucleotide position 448, causing the aspartic acid (D) at amino acid position 150 to be replaced by a tyrosine (Y). 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	0.11
BayesDel_addAF	Benign	0.0063	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	3.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	.;T;T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	0.012	D
MutationAssessor	Benign	1.7	L;L;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.9	D;D;.;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D;D;.;.;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		0.98	.;.;.;.;D
Vest4		0.20
MutPred		0.46		Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);.;.;.;
MVP		0.66
MPC		0.098
ClinPred		0.65	D
GERP RS		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.37		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1282795748; hg19: chr2-231226337;