7-135164898-G-C

Position:

• chr7-135164898-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018295.5(TMEM140):​c.457G>C​(p.Ala153Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM140 NM_018295.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56

Genes affected

TMEM140 (HGNC:21870): (transmembrane protein 140) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CYREN (HGNC:):

CYREN (HGNC:22432): (cell cycle regulator of NHEJ) Involved in double-strand break repair via nonhomologous end joining and negative regulation of double-strand break repair via nonhomologous end joining. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM140	NM_018295.5	c.457G>C	p.Ala153Pro	missense_variant	2/2	ENST00000275767.3	NP_060765.4
CYREN	NM_001305630.2	c.174+3851C>G		intron_variant			NP_001292559.1
CYREN	XM_017012595.2	c.*40+2834C>G		intron_variant			XP_016868084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM140	ENST00000275767.3	c.457G>C	p.Ala153Pro	missense_variant	2/2	1	NM_018295.5	ENSP00000275767.2
CYREN	ENST00000459937.5	n.356+3851C>G		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2024

The c.457G>C (p.A153P) alteration is located in exon 2 (coding exon 1) of the TMEM140 gene. This alteration results from a G to C substitution at nucleotide position 457, causing the alanine (A) at amino acid position 153 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.19
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.29		Loss of stability (P = 0.0704);
MVP		0.15
MPC		0.73
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.82
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-134849650;