Genetic Variant NM_198153.3:c.66T>C (chr6-41228716-T-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

2 publications found

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:

ENSG00000290563 (HGNC:):

ENSG00000290563 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198153.3. 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
	TREML4	NM_198153.3	MANE Select	c.66T>C	p.Gly22Gly	splice_region synonymous	Exon 2 of 6	NP_937796.1	Q6UXN2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TREML4	ENST00000341495.7	TSL:1 MANE Select	c.66T>C	p.Gly22Gly	splice_region synonymous	Exon 2 of 6	ENSP00000342570.2	Q6UXN2
TREML4	ENST00000448827.6	TSL:1	c.66T>C	p.Gly22Gly	splice_region synonymous	Exon 2 of 6	ENSP00000418078.1	Q6UXN2
ENSG00000290563	ENST00000564680.6	TSL:1	n.206-10722A>G		intron	N/A

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

GnomAD2 exomes

AF:

0.00386

AC:

959

AN:

248672

AF XY:

0.00402

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 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

African (AFR)

AF:

0.000568

AC:

AN:

33426

American (AMR)

AF:

0.00200

AC:

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

806

AN:

25938

East Asian (EAS)

AF:

0.000151

AC:

AN:

39680

South Asian (SAS)

AF:

0.00130

AC:

112

AN:

86086

European-Finnish (FIN)

AF:

0.00101

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00938

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00333

AC:

3699

AN:

1110466

Other (OTH)

AF:

0.00463

AC:

279

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

260

520

780

1040

1300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00361

AC:

549

AN:

152022

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

41450

American (AMR)

AF:

0.00334

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

122

AN:

3464

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00229

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00465

AC:

316

AN:

67944

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.044

(source)

DANN

Benign

0.37

PhyloP100

-2.4

PromoterAI

0.0016

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over