NM_025124.4:c.173A>T

Variant names:

• chr11-67469020-T-A
• rs1353147768
• NM_025124.4:c.173A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_025124.4(TMEM134):​c.173A>T​(p.Gln58Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,346,608 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q58P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TMEM134 NM_025124.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40
• Publications: 0 publications found

Genes affected

TMEM134 (HGNC:26142): (transmembrane protein 134) Located in cytosol and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

AIP (HGNC:358): (aryl hydrocarbon receptor interacting protein) The protein encoded by this gene is a receptor for aryl hydrocarbons and a ligand-activated transcription factor. The encoded protein is found in the cytoplasm as part of a multiprotein complex, but upon binding of ligand is transported to the nucleus. This protein can regulate the expression of many xenobiotic metabolizing enzymes. Also, the encoded protein can bind specifically to and inhibit the activity of hepatitis B virus. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

AIP Gene-Disease associations (from GenCC):

• growth hormone secreting pituitary adenoma 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial isolated pituitary adenoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acromegaly

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025124.4. 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
	TMEM134	NM_025124.4	MANE Select	c.173A>T	p.Gln58Leu	missense splice_region	Exon 1 of 7	NP_079400.1	Q9H6X4-1
	TMEM134	NM_001078651.3		c.173A>T	p.Gln58Leu	missense splice_region	Exon 1 of 7	NP_001072119.1
	TMEM134	NM_001078650.3		c.173A>T	p.Gln58Leu	missense splice_region	Exon 1 of 6	NP_001072118.1	Q9H6X4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM134	ENST00000308022.7	TSL:2 MANE Select	c.173A>T	p.Gln58Leu	missense splice_region	Exon 1 of 7	ENSP00000312615.2	Q9H6X4-1
	TMEM134	ENST00000393877.3	TSL:1	c.173A>T	p.Gln58Leu	missense splice_region	Exon 1 of 6	ENSP00000377455.3	Q9H6X4-2
	TMEM134	ENST00000501408.6	TSL:1	n.217A>T		splice_region non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1346608 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 664564

⚠️ 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: 27566

American (AMR) AF: 0.0000311 AC: 1 AN: 32186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23824

East Asian (EAS) AF: 0.00 AC: 0 AN: 29820

South Asian (SAS) AF: 0.00 AC: 0 AN: 76336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057044

Other (OTH) AF: 0.00 AC: 0 AN: 55648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.078	T
Polyphen		0.97	D
Vest4		0.52
MutPred		0.51		Loss of solvent accessibility (P = 0.0635)
MVP		0.25
MPC		0.35
ClinPred		0.92	D
GERP RS		3.1
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.53
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.19		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: rs1353147768; hg19: chr11-67236491;