8-70596318-T-C

Variant names:

• chr8-70596318-T-C
• rs34159261
• NM_014294.6:c.430A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_014294.6(TRAM1):​c.430A>G​(p.Asn144Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,593,514 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (31 hom.)
• Consequence: TRAM1 NM_014294.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.86
• Publications: 5 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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-70596318-T-C is Benign according to our data. Variant chr8-70596318-T-C is described in ClinVar as [Benign]. Clinvar id is 789603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1787/152264) while in subpopulation AFR AF = 0.0395 (1640/41542). AF 95% confidence interval is 0.0379. There are 32 homozygotes in GnomAd4. There are 838 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6	c.430A>G	p.Asn144Asp	missense_variant	Exon 5 of 11	ENST00000262213.7	NP_055109.1
TRAM1	NM_001317804.2	c.337A>G	p.Asn113Asp	missense_variant	Exon 6 of 12		NP_001304733.1
TRAM1	NM_001317805.2	c.172A>G	p.Asn58Asp	missense_variant	Exon 5 of 11		NP_001304734.1
TRAM1	XM_047421636.1	c.172A>G	p.Asn58Asp	missense_variant	Exon 6 of 12		XP_047277592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM1	ENST00000262213.7	c.430A>G	p.Asn144Asp	missense_variant	Exon 5 of 11	1	NM_014294.6	ENSP00000262213.2
TRAM1	ENST00000521425.5	c.172A>G	p.Asn58Asp	missense_variant	Exon 5 of 11	2		ENSP00000428052.1
TRAM1	ENST00000520700.1	n.397A>G		non_coding_transcript_exon_variant	Exon 5 of 6	5
TRAM1	ENST00000521049.5	n.444+1577A>G		intron_variant	Intron 3 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1770 AN: 152146 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00308 AC: 714 AN: 231946 AF XY: 0.00229

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00355

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000400

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00131 AC: 1884 AN: 1441250 Hom.: 31 Cov.: 29 AF XY: 0.00117 AC XY: 837 AN XY: 716852

African (AFR) AF: 0.0373 AC: 1187 AN: 31818

American (AMR) AF: 0.00291 AC: 119 AN: 40944

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 71 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 38118

South Asian (SAS) AF: 0.0000970 AC: 8 AN: 82512

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53048

Middle Eastern (MID) AF: 0.00350 AC: 20 AN: 5714

European-Non Finnish (NFE) AF: 0.000264 AC: 291 AN: 1103796

Other (OTH) AF: 0.00312 AC: 186 AN: 59606

GnomAD4 genome AF: 0.0117 AC: 1787 AN: 152264 Hom.: 32 Cov.: 32 AF XY: 0.0113 AC XY: 838 AN XY: 74454

African (AFR) AF: 0.0395 AC: 1640 AN: 41542

American (AMR) AF: 0.00575 AC: 88 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67994

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00404 Hom.: 18

Bravo AF: 0.0129

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0365 AC: 161

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00395 AC: 480

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T
Eigen	Benign	0.022
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	.;L
PhyloP100		1.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.22	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.33	.;B
Vest4		0.27
MVP		0.34
MPC		0.44
ClinPred		0.035	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.68
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34159261; hg19: chr8-71508553;