7-887508-C-T

Variant names:

• chr7-887508-C-T
• rs149811092
• NM_015949.3:c.455C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_015949.3(GET4):​c.455C>T​(p.Thr152Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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. T152S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GET4 NM_015949.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.92
• 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 2 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=0.38894886).

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.455C>T	p.Thr152Ile	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.455C>T	p.Thr152Ile	missense	Exon 4 of 9	ENSP00000265857.3	Q7L5D6-1
	GET4	ENST00000407192.5	TSL:1	c.296C>T	p.Thr99Ile	missense	Exon 3 of 8	ENSP00000385646.1	Q7L5D6-2
	GET4	ENST00000919176.1		c.473C>T	p.Thr158Ile	missense	Exon 4 of 9	ENSP00000589235.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.73	N
PhyloP100		5.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.66	N
REVEL	Benign	0.19
Sift	Benign	0.87	T
Sift4G	Benign	0.94	T
Polyphen		0.013	B
Vest4		0.51
MutPred		0.58		Gain of methylation at K155 (P = 0.1235)
MVP		0.23
MPC		0.23
ClinPred		0.64	D
GERP RS		5.6
PromoterAI		0.0075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.30
gMVP		0.32
Mutation Taster		=30/70	disease causing

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: rs149811092; hg19: chr7-927145; COSMIC: COSV105057007; COSMIC: COSV105057007;