7-135164448-G-A

Variant names:

• chr7-135164448-G-A
• rs776496054
• NM_018295.5:c.7G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_018295.5(TMEM140):​c.7G>A​(p.Gly3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,596,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: TMEM140 NM_018295.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.11
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021033227).
• BP6: Variant 7-135164448-G-A is Benign according to our data. Variant chr7-135164448-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3178806.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018295.5. 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
	TMEM140	NM_018295.5	MANE Select	c.7G>A	p.Gly3Ser	missense	Exon 2 of 2	NP_060765.4	Q9NV12
	CYREN	NM_001305630.2		c.174+4301C>T		intron	N/A	NP_001292559.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM140	ENST00000275767.3	TSL:1 MANE Select	c.7G>A	p.Gly3Ser	missense	Exon 2 of 2	ENSP00000275767.2	Q9NV12
	CYREN	ENST00000459937.5	TSL:1	n.356+4301C>T		intron	N/A
	TMEM140	ENST00000873393.1		c.7G>A	p.Gly3Ser	missense	Exon 2 of 2	ENSP00000543452.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 250116 AF XY: 0.0000222

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000194 AC: 28 AN: 1444512 Hom.: 0 Cov.: 29 AF XY: 0.0000182 AC XY: 13 AN XY: 714256

African (AFR) AF: 0.0000603 AC: 2 AN: 33188

American (AMR) AF: 0.0000450 AC: 2 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39130

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000173 AC: 19 AN: 1097314

Other (OTH) AF: 0.0000504 AC: 3 AN: 59532

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74498

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0020
DANN	Benign	0.78
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.021
Sift	Benign	0.81	T
Sift4G	Benign	0.86	T
Polyphen		0.014	B
Vest4		0.065
MutPred		0.11		Gain of glycosylation at G3 (P = 0.0136)
MVP		0.014
MPC		0.15
ClinPred		0.030	T
GERP RS		-11
Varity_R		0.030
gMVP		0.17
Mutation Taster		=100/0	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: rs776496054; hg19: chr7-134849200; COSMIC: COSV51967214; COSMIC: COSV51967214;