11-87038071-C-G

Variant names:

• chr11-87038071-C-G
• rs145333093
• NM_022918.4:c.26C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_022918.4(TMEM135):​c.26C>G​(p.Pro9Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000515 in 1,614,206 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: TMEM135 NM_022918.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.35
• Publications: 0 publications found

Genes affected

TMEM135 (HGNC:26167): (transmembrane protein 135) Predicted to be involved in peroxisome organization. Predicted to act upstream of or within response to cold and response to food. Predicted to be located in mitochondrion and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

TMEM135 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00823316).
• BP6: Variant 11-87038071-C-G is Benign according to our data. Variant chr11-87038071-C-G is described in ClinVar as Benign. ClinVar VariationId is 3053201.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022918.4. 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
	TMEM135	NM_022918.4	MANE Select	c.26C>G	p.Pro9Arg	missense	Exon 1 of 15	NP_075069.3
	TMEM135	NM_001168724.2		c.26C>G	p.Pro9Arg	missense	Exon 1 of 14	NP_001162195.1	Q86UB9-2
	TMEM135	NR_033149.2		n.138C>G		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM135	ENST00000305494.6	TSL:1 MANE Select	c.26C>G	p.Pro9Arg	missense	Exon 1 of 15	ENSP00000306344.5	Q86UB9-1
	TMEM135	ENST00000340353.11	TSL:1	c.26C>G	p.Pro9Arg	missense	Exon 1 of 14	ENSP00000345513.6	Q86UB9-2
	TMEM135	ENST00000954970.1		c.26C>G	p.Pro9Arg	missense	Exon 1 of 16	ENSP00000625029.1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152204 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000771 AC: 194 AN: 251480 AF XY: 0.000522

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000260 AC: 380 AN: 1461884 Hom.: 3 Cov.: 32 AF XY: 0.000209 AC XY: 152 AN XY: 727246

African (AFR) AF: 0.00959 AC: 321 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112010

Other (OTH) AF: 0.000497 AC: 30 AN: 60396

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152322 Hom.: 4 Cov.: 31 AF XY: 0.00309 AC XY: 230 AN XY: 74484

African (AFR) AF: 0.0102 AC: 426 AN: 41582

American (AMR) AF: 0.00118 AC: 18 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000390 Hom.: 0

Bravo AF: 0.00321

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000988 AC: 120

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TMEM135-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.13
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.017	D
Polyphen		0.88	P
Vest4		0.85
MVP		0.043
MPC		0.69
ClinPred		0.070	T
GERP RS		5.1
PromoterAI		0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.81
Mutation Taster		=167/133	polymorphism

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

Other links and lift over

dbSNP: rs145333093; hg19: chr11-86749113;