chr7-135164709-T-C

Position:

• chr7-135164709-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018295.5(TMEM140):​c.268T>C​(p.Ser90Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TMEM140 NM_018295.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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: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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09665769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM140	NM_018295.5	c.268T>C	p.Ser90Pro	missense_variant	2/2	ENST00000275767.3
CYREN	NM_001305630.2	c.174+4040A>G		intron_variant
CYREN	XM_017012595.2	c.*40+3023A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM140	ENST00000275767.3	c.268T>C	p.Ser90Pro	missense_variant	2/2	1	NM_018295.5	P1
CYREN	ENST00000459937.5	n.356+4040A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 89

GnomAD4 genome Cov.: 34

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

Feb 23, 2023

The c.268T>C (p.S90P) alteration is located in exon 2 (coding exon 1) of the TMEM140 gene. This alteration results from a T to C substitution at nucleotide position 268, causing the serine (S) at amino acid position 90 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	0.40
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.14
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.033	D
Polyphen		0.14	B
Vest4		0.17
MutPred		0.32		Loss of catalytic residue at S90 (P = 0.01);
MVP		0.055
MPC		0.23
ClinPred		0.44	T
GERP RS		4.4
Varity_R		0.47
gMVP		0.59

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: chr7-134849461;