Genetic Variant NM_021637.3:c.120+7G>A (chrX-101079129-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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

Publications

0 publications found

Variant links:

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]

TMEM35A links:

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

TRMT2B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 2661049.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 12 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021637.3. 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
	TMEM35A	NM_021637.3	MANE Select	c.120+7G>A		splice_region intron	N/A	NP_067650.1	Q53FP2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM35A	ENST00000372930.5	TSL:1 MANE Select	c.120+7G>A		splice_region intron	N/A	ENSP00000362021.4	Q53FP2
	TRMT2B-AS1	ENST00000443801.2	TSL:5	n.113+15235C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000458

AC:

AN:

111444

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000559

AC:

100

AN:

178757

AF XY:

0.000500

show subpopulations

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 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.:

Cov.:

AF XY:

0.000660

AC XY:

239

AN XY:

362315

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26395

American (AMR)

AF:

0.000256

AC:

AN:

35098

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

19352

East Asian (EAS)

AF:

0.00

AC:

AN:

30171

South Asian (SAS)

AF:

0.00

AC:

AN:

53882

European-Finnish (FIN)

AF:

0.0000994

AC:

AN:

40237

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.000790

AC:

665

AN:

841553

Other (OTH)

AF:

0.000804

AC:

AN:

46042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000458

AC:

AN:

111444

Hom.:

Cov.:

AF XY:

0.000357

AC XY:

AN XY:

33624

show subpopulations

African (AFR)

AF:

0.0000978

AC:

AN:

30660

American (AMR)

AF:

0.0000956

AC:

AN:

10460

Ashkenazi Jewish (ASJ)

AF:

0.00341

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3523

South Asian (SAS)

AF:

0.00

AC:

AN:

2636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000697

AC:

AN:

53068

Other (OTH)

AF:

0.000666

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000408

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.4

(source)

DANN

Benign

0.55

PhyloP100

0.17

PromoterAI

0.029

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over