rs139780486

Variant names:

• chr7-887504-C-G
• rs139780486
• NM_015949.3:c.451C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-887504-C-G
• chr7-887504-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_015949.3(GET4):​c.451C>G​(p.Leu151Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L151F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GET4 NM_015949.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81
• Publications: 0 publications found

Genes affected

GET4 (HGNC:21690): (guided entry of tail-anchored proteins factor 4) Enables chaperone binding activity. Involved in cytoplasmic sequestering of protein; maintenance of unfolded protein involved in ERAD pathway; and tail-anchored membrane protein insertion into ER membrane. Located in chromosome; cytosol; and nuclear lumen. Part of BAT3 complex. [provided by Alliance of Genome Resources, Apr 2022]

SUN1 (HGNC:18587): (Sad1 and UNC84 domain containing 1) This gene is a member of the unc-84 homolog family and encodes a nuclear envelope protein with an Unc84 (SUN) domain. The protein is involved in nuclear anchorage and migration. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2019]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.16812 (below the threshold of 3.09). Trascript score misZ: -2.2826 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital disorder of glycosylation, type IIy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17815202).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015949.3. 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
	GET4	NM_015949.3	MANE Select	c.451C>G	p.Leu151Val	missense	Exon 4 of 9	NP_057033.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET4	ENST00000265857.8	TSL:1 MANE Select	c.451C>G	p.Leu151Val	missense	Exon 4 of 9	ENSP00000265857.3	Q7L5D6-1
	GET4	ENST00000407192.5	TSL:1	c.292C>G	p.Leu98Val	missense	Exon 3 of 8	ENSP00000385646.1	Q7L5D6-2
	GET4	ENST00000919176.1		c.469C>G	p.Leu157Val	missense	Exon 4 of 9	ENSP00000589235.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000508 AC: 1 AN: 196898 AF XY: 0.00000944

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: 0.00

Gnomad OTH exome AF: 0.000218

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395540 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688998

African (AFR) AF: 0.00 AC: 0 AN: 31134

American (AMR) AF: 0.00 AC: 0 AN: 33960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22226

East Asian (EAS) AF: 0.00 AC: 0 AN: 38526

South Asian (SAS) AF: 0.00 AC: 0 AN: 76484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49466

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080794

Other (OTH) AF: 0.00 AC: 0 AN: 57520

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000240 Hom.: 0

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	0.066
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.022
Sift	Benign	0.61	T
Sift4G	Benign	0.33	T
Polyphen		0.0020	B
Vest4		0.16
MutPred		0.34		Loss of stability (P = 0.0895)
MVP		0.12
MPC		0.21
ClinPred		0.17	T
GERP RS		3.5
PromoterAI		-0.0099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.092
gMVP		0.10
Mutation Taster		=76/24	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: rs139780486; hg19: chr7-927141;