chr4-117084948-G-T

Variant names:

• chr4-117084948-G-T
• rs1732422164
• NM_152402.3:c.446C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152402.3(TRAM1L1):​c.446C>A​(p.Pro149Gln) 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 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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: 0.0000014 (0 hom.)
• Consequence: TRAM1L1 NM_152402.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.447
• Publications: 0 publications found

Genes affected

TRAM1L1 (HGNC:28371): (translocation associated membrane protein 1 like 1) Predicted to be involved in protein insertion into ER membrane. Predicted to be integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC105377388 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152402.3. 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
	TRAM1L1	NM_152402.3	MANE Select	c.446C>A	p.Pro149Gln	missense	Exon 1 of 1	NP_689615.2	Q8N609

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAM1L1	ENST00000310754.5	TSL:6 MANE Select	c.446C>A	p.Pro149Gln	missense	Exon 1 of 1	ENSP00000309402.4	Q8N609

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

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: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

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	0.27
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.0020
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.45
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.24
Sift	Benign	0.060	T
Sift4G	Uncertain	0.040	D
Polyphen		0.98	D
Vest4		0.50
MutPred		0.63		Gain of catalytic residue at P149 (P = 0.0707)
MVP		0.50
MPC		0.75
ClinPred		0.93	D
GERP RS		3.2
Varity_R		0.16
gMVP		0.34
Mutation Taster		=78/22	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: rs1732422164; hg19: chr4-118006104;