Genetic Variant TREML4:p.Gly22Gly (chr6-41228716-T-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_198153.3(TREML4):c.66T>C(p.Gly22Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,611,498 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0035 ( 20 hom. )

Consequence

TREML4
NM_198153.3 splice_region, synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.41

Variant links:

Genes affected

TREML4 (HGNC:30807): (triggering receptor expressed on myeloid cells like 4) Predicted to enable signaling receptor activity. Involved in positive regulation of toll-like receptor 7 signaling pathway. Predicted to be located in endoplasmic reticulum. Predicted to be active in cell surface. Predicted to colocalize with endosome membrane and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

TREML4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 6-41228716-T-C is Benign according to our data. Variant chr6-41228716-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1176822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.41 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREML4	NM_198153.3 link	c.66T>C	p.Gly22Gly	splice_region_variant, synonymous_variant	Exon 2 of 6	ENST00000341495.7	NP_937796.1	Q6UXN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TREML4	ENST00000341495.7 link	c.66T>C	p.Gly22Gly	splice_region_variant, synonymous_variant	Exon 2 of 6	1	NM_198153.3	ENSP00000342570.2	Q6UXN2
TREML4	ENST00000448827.6 link	c.66T>C	p.Gly22Gly	splice_region_variant, synonymous_variant	Exon 2 of 6	1		ENSP00000418078.1	Q6UXN2
TREML4	ENST00000461240.1 link	n.-241T>C		upstream_gene_variant		2		ENSP00000418480.1	H7C4X5

Frequencies

GnomAD3 genomes

AF:

0.00362

AC:

550

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000629

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.0352

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00465

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00386

AC:

959

AN:

248672

Hom.:

AF XY:

0.00402

AC XY:

541

AN XY:

134452

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00233

Gnomad ASJ exome

AF:

0.0313

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.00431

Gnomad OTH exome

AF:

0.00609

GnomAD4 exome

AF:

0.00351

AC:

5118

AN:

1459476

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

2652

AN XY:

725822

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00200

Gnomad4 ASJ exome

AF:

0.0311

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00130

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00333

Gnomad4 OTH exome

AF:

0.00463

GnomAD4 genome

AF:

0.00361

AC:

549

AN:

152022

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000627

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.0352

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00465

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00557

Hom.:

Bravo

AF:

0.00333

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00421

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.044

DANN

Benign

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over