10-11463057-C-G

Variant names:

• chr10-11463057-C-G
• rs1280325776
• NM_014688.5:c.1871G>C

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.1871G>C​(p.Arg624Pro) 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 1,461,706 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R624Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP6NL NM_014688.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.677
• 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=0.08765715).

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.1871G>C	p.Arg624Pro	missense	Exon 15 of 15	NP_055503.1	Q92738-1
	USP6NL	NM_001391959.1		c.1940G>C	p.Arg647Pro	missense	Exon 14 of 14	NP_001378888.1	X6RAB3
	USP6NL	NM_001080491.5		c.1922G>C	p.Arg641Pro	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.1871G>C	p.Arg624Pro	missense	Exon 15 of 15	ENSP00000476462.1	Q92738-1
	USP6NL	ENST00000938640.1		c.1991G>C	p.Arg664Pro	missense	Exon 17 of 17	ENSP00000608699.1
	USP6NL	ENST00000938639.1		c.1949G>C	p.Arg650Pro	missense	Exon 16 of 16	ENSP00000608698.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249108 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111870

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.2
DANN	Benign	0.64
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.68
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.025
Sift	Uncertain	0.028	D
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.052
MutPred		0.33		Loss of methylation at R624 (P = 0.0394)
MVP		0.31
MPC		0.18
ClinPred		0.045	T
GERP RS		-5.4
Varity_R		0.077
gMVP		0.19
Mutation Taster		=94/6	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: rs1280325776; hg19: chr10-11505056;