rs761960464

Variant names:

• chr8-70583235-G-A
• rs761960464
• NM_014294.6:c.980C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-70583235-G-A
• chr8-70583235-G-C

Variant summary

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

The NM_014294.6(TRAM1):​c.980C>T​(p.Ser327Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: TRAM1 NM_014294.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12
• Publications: 0 publications found

Genes affected

TRAM1 (HGNC:20568): (translocation associated membrane protein 1) This gene encodes a multi-pass membrane protein that is part of the mammalian endoplasmic reticulum. The encoded protein influences glycosylation and facilitates the translocation of secretory proteins across the endoplasmic reticulum membrane by regulating which domains of the nascent polypeptide chain are visible to the cytosol during a translocational pause. [provided by RefSeq, Oct 2009]

ENSG00000298363 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3367377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6	c.980C>T	p.Ser327Phe	missense_variant	Exon 10 of 11	ENST00000262213.7	NP_055109.1
TRAM1	NM_001317804.2	c.887C>T	p.Ser296Phe	missense_variant	Exon 11 of 12		NP_001304733.1
TRAM1	NM_001317805.2	c.722C>T	p.Ser241Phe	missense_variant	Exon 10 of 11		NP_001304734.1
TRAM1	XM_047421636.1	c.722C>T	p.Ser241Phe	missense_variant	Exon 11 of 12		XP_047277592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM1	ENST00000262213.7	c.980C>T	p.Ser327Phe	missense_variant	Exon 10 of 11	1	NM_014294.6	ENSP00000262213.2
TRAM1	ENST00000521425.5	c.722C>T	p.Ser241Phe	missense_variant	Exon 10 of 11	2		ENSP00000428052.1
ENSG00000298363	ENST00000755107.1	n.611G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251200 AF XY: 0.00000737

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: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461704 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727128

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.980C>T (p.S327F) alteration is located in exon 10 (coding exon 10) of the TRAM1 gene. This alteration results from a C to T substitution at nucleotide position 980, causing the serine (S) at amino acid position 327 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	0.18
BayesDel_addAF	Benign	0.0093	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		5.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.13
Sift	Benign	0.099	T;T
Sift4G	Uncertain	0.045	D;D
Polyphen		0.91	.;P
Vest4		0.52
MutPred		0.30		.;Loss of disorder (P = 0.0326);
MVP		0.28
MPC		0.81
ClinPred		0.83	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.77
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs761960464; hg19: chr8-71495470;