10-11462529-G-A

Variant names:

• chr10-11462529-G-A
• rs372926533
• NM_014688.5:c.2399C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014688.5(USP6NL):​c.2399C>T​(p.Ser800Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (1 hom.)
• Consequence: USP6NL NM_014688.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

Genes affected

USP6NL (HGNC:16858): (USP6 N-terminal like) Enables GTPase activator activity and small GTPase binding activity. Involved in several processes, including plasma membrane to endosome transport; positive regulation of GTPase activity; and retrograde transport, plasma membrane to Golgi. Located in cytoplasmic vesicle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27293336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP6NL	NM_014688.5	c.2399C>T	p.Ser800Phe	missense_variant	Exon 15 of 15	ENST00000609104.6	NP_055503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP6NL	ENST00000609104.6	c.2399C>T	p.Ser800Phe	missense_variant	Exon 15 of 15	1	NM_014688.5	ENSP00000476462.1
USP6NL	ENST00000379237.6	c.2468C>T	p.Ser823Phe	missense_variant	Exon 14 of 14	5		ENSP00000368539.2
USP6NL	ENST00000277575.5	c.2450C>T	p.Ser817Phe	missense_variant	Exon 14 of 14	5		ENSP00000277575.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461708 Hom.: 1 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727136

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2450C>T (p.S817F) alteration is located in exon 14 (coding exon 14) of the USP6NL gene. This alteration results from a C to T substitution at nucleotide position 2450, causing the serine (S) at amino acid position 817 to be replaced by a phenylalanine (F). 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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T;.;.
Eigen	Benign	-0.0015
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.95	.;N;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	.;D;.
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.47	P;P;.
Vest4		0.14
MutPred		0.28		Loss of glycosylation at S800 (P = 1e-04);.;.;
MVP		0.64
MPC		0.29
ClinPred		0.44	T
GERP RS		6.0
Varity_R		0.16
gMVP		0.15

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: rs372926533; hg19: chr10-11504528;