NM_014688.5:c.1859A>C

Variant names:

• chr10-11463069-T-G
• NM_014688.5:c.1859A>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.1859A>C​(p.Asp620Ala) 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 1,461,704 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: 1.75
• 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=0.10580975).

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.1859A>C	p.Asp620Ala	missense	Exon 15 of 15	NP_055503.1	Q92738-1
	USP6NL	NM_001391959.1		c.1928A>C	p.Asp643Ala	missense	Exon 14 of 14	NP_001378888.1	X6RAB3
	USP6NL	NM_001080491.5		c.1910A>C	p.Asp637Ala	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.1859A>C	p.Asp620Ala	missense	Exon 15 of 15	ENSP00000476462.1	Q92738-1
	USP6NL	ENST00000938640.1		c.1979A>C	p.Asp660Ala	missense	Exon 17 of 17	ENSP00000608699.1
	USP6NL	ENST00000938639.1		c.1937A>C	p.Asp646Ala	missense	Exon 16 of 16	ENSP00000608698.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461704 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727132

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: 53394

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111870

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

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	0.092
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.047
Sift	Benign	0.051	T
Sift4G	Uncertain	0.058	T
Polyphen		0.0020	B
Vest4		0.045
MutPred		0.15		Gain of methylation at R624 (P = 0.145)
MVP		0.56
MPC		0.16
ClinPred		0.27	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.32
Mutation Taster		=93/7	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

hg19: chr10-11505068;