10-11462899-C-A

Variant names:

• chr10-11462899-C-A
• rs532786099
• NM_014688.5:c.2029G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014688.5(USP6NL):​c.2029G>T​(p.Val677Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 6.8e-7 (0 hom.)
• Consequence: USP6NL NM_014688.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.24
• Publications: 0 publications found

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]

ENSG00000301463 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08870536).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014688.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP6NL	NM_014688.5	MANE Select	c.2029G>T	p.Val677Phe	missense	Exon 15 of 15	NP_055503.1	Q92738-1
	USP6NL	NM_001391959.1		c.2098G>T	p.Val700Phe	missense	Exon 14 of 14	NP_001378888.1	X6RAB3
	USP6NL	NM_001080491.5		c.2080G>T	p.Val694Phe	missense	Exon 14 of 14	NP_001073960.1	Q92738-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP6NL	ENST00000609104.6	TSL:1 MANE Select	c.2029G>T	p.Val677Phe	missense	Exon 15 of 15	ENSP00000476462.1	Q92738-1
	USP6NL	ENST00000938640.1		c.2149G>T	p.Val717Phe	missense	Exon 17 of 17	ENSP00000608699.1
	USP6NL	ENST00000938639.1		c.2107G>T	p.Val703Phe	missense	Exon 16 of 16	ENSP00000608698.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461284 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726876

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111670

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0050
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-2.2
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.049	D
Polyphen		0.69	P
Vest4		0.076
MutPred		0.081		Loss of glycosylation at S673 (P = 0.1219)
MVP		0.23
MPC		0.37
ClinPred		0.89	D
GERP RS		-9.2
Varity_R		0.080
gMVP		0.36
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs532786099; hg19: chr10-11504898;