4-117084943-G-A

Variant names:

• chr4-117084943-G-A
• rs899507460
• NM_152402.3:c.451C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152402.3(TRAM1L1):​c.451C>T​(p.Leu151Phe) 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 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: TRAM1L1 NM_152402.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.319

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.198268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1L1	NM_152402.3	c.451C>T	p.Leu151Phe	missense_variant	Exon 1 of 1	ENST00000310754.5	NP_689615.2
LOC105377388	XR_939103.3	n.2572-1382G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM1L1	ENST00000310754.5	c.451C>T	p.Leu151Phe	missense_variant	Exon 1 of 1	6	NM_152402.3	ENSP00000309402.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.451C>T (p.L151F) alteration is located in exon 1 (coding exon 1) of the TRAM1L1 gene. This alteration results from a C to T substitution at nucleotide position 451, causing the leucine (L) at amino acid position 151 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.1
DANN	Benign	0.47
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.21
Sift	Benign	0.31	T
Sift4G	Benign	0.15	T
Polyphen		0.0030	B
Vest4		0.098
MutPred		0.31		Gain of helix (P = 0.062);
MVP		0.41
MPC		0.28
ClinPred		0.060	T
GERP RS		2.3
Varity_R		0.058
gMVP		0.058

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

Publications

LitVar

Other links and lift over

dbSNP: rs899507460; hg19: chr4-118006099;