chrX-101079129-G-A

Variant names:

• chrX-101079129-G-A
• rs374716786
• NM_021637.3:c.120+7G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021637.3(TMEM35A):​c.120+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 1,208,307 control chromosomes in the GnomAD database, including 1 homozygotes. There are 251 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., 12 hem., cov: 23)
  • Exomes 𝑓: 0.00069 (0 hom. 239 hem.)
• Consequence: TMEM35A NM_021637.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001100
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.169

Genes affected

TMEM35A (HGNC:25864): (transmembrane protein 35A) Enables acetylcholine receptor regulator activity. Involved in chaperone-mediated protein complex assembly and positive regulation of protein localization to cell surface. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

TRMT2B-AS1 (HGNC:41116): (TRMT2B antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-101079129-G-A is Benign according to our data. Variant chrX-101079129-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2661049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM35A	NM_021637.3	c.120+7G>A		splice_region_variant, intron_variant	Intron 1 of 1	ENST00000372930.5	NP_067650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM35A	ENST00000372930.5	c.120+7G>A		splice_region_variant, intron_variant	Intron 1 of 1	1	NM_021637.3	ENSP00000362021.4
TRMT2B-AS1	ENST00000443801.2	n.113+15235C>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.000458 AC: 51 AN: 111444 Hom.: 1 Cov.: 23 AF XY: 0.000357 AC XY: 12 AN XY: 33624

Gnomad AFR AF: 0.0000978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

Gnomad ASJ AF: 0.00341

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000697

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.000559 AC: 100 AN: 178757 Hom.: 0 AF XY: 0.000500 AC XY: 32 AN XY: 64003

Gnomad AFR exome AF: 0.0000771

Gnomad AMR exome AF: 0.000221

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000130

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000690 AC: 757 AN: 1096863 Hom.: 0 Cov.: 30 AF XY: 0.000660 AC XY: 239 AN XY: 362315

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000994

Gnomad4 NFE exome AF: 0.000790

Gnomad4 OTH exome AF: 0.000804

GnomAD4 genome AF: 0.000458 AC: 51 AN: 111444 Hom.: 1 Cov.: 23 AF XY: 0.000357 AC XY: 12 AN XY: 33624

Gnomad4 AFR AF: 0.0000978

Gnomad4 AMR AF: 0.0000956

Gnomad4 ASJ AF: 0.00341

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000697

Gnomad4 OTH AF: 0.000666

Alfa AF: 0.00120 Hom.: 12

Bravo AF: 0.000408

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMEM35A: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.4
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.012
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

LitVar

Other links and lift over

dbSNP: rs374716786; hg19: chrX-100334118;