7-135164564-C-A

Position:

• chr7-135164564-C-A

Variant summary

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

The NM_018295.5(TMEM140):​c.123C>A​(p.Asp41Glu) 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. 14/21 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: 0.337

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=0.07825652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM140	NM_018295.5	c.123C>A	p.Asp41Glu	missense_variant	2/2	ENST00000275767.3	NP_060765.4
CYREN	NM_001305630.2	c.174+4185G>T		intron_variant			NP_001292559.1
CYREN	XM_017012595.2	c.*40+3168G>T		intron_variant			XP_016868084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM140	ENST00000275767.3	c.123C>A	p.Asp41Glu	missense_variant	2/2	1	NM_018295.5	ENSP00000275767	P1
CYREN	ENST00000459937.5	n.356+4185G>T		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 05, 2024

The c.123C>A (p.D41E) alteration is located in exon 2 (coding exon 1) of the TMEM140 gene. This alteration results from a C to A substitution at nucleotide position 123, causing the aspartic acid (D) at amino acid position 41 to be replaced by a glutamic acid (E). 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	Benign	0.29
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.3
DANN	Benign	0.95
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.066
Sift	Benign	0.34	T
Sift4G	Uncertain	0.018	D
Polyphen		0.096	B
Vest4		0.041
MutPred		0.46		Gain of methylation at R46 (P = 0.3749);
MVP		0.099
MPC		0.17
ClinPred		0.28	T
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.12

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: chr7-134849316;