Genetic Variant NM_013322.3:c.25-5T>C (chr7-26360970-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_013322.3(SNX10):c.25-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,613,046 control chromosomes in the GnomAD database, including 13 homozygotes. 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 Benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 13 hom. )

Consequence

SNX10
NM_013322.3 splice_region, intron

Scores

Splicing: ADA: 0.05199

Clinical Significance

Benign criteria provided, single submitter B:4

Conservation

PhyloP100: 2.67

Publications

5 publications found

Variant links:

Genes affected

SNX10 (HGNC:14974): (sorting nexin 10) This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members. This gene may play a role in regulating endosome homeostasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

SNX10 Gene-Disease associations (from GenCC):

autosomal recessive osteopetrosis 8
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia
autosomal recessive osteopetrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SNX10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 7-26360970-T-C is Benign according to our data. Variant chr7-26360970-T-C is described in ClinVar as Benign. ClinVar VariationId is 725914.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (304/152318) while in subpopulation NFE AF = 0.00201 (137/68028). AF 95% confidence interval is 0.00174. There are 0 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013322.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SNX10	NM_013322.3	MANE Select	c.25-5T>C		splice_region intron	N/A	NP_037454.2
SNX10	NM_001199837.3		c.11T>C	p.Leu4Ser	missense	Exon 1 of 5	NP_001186766.1
SNX10	NM_001318198.1		c.103-5T>C		splice_region intron	N/A	NP_001305127.1	Q9Y5X0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SNX10	ENST00000338523.9	TSL:1 MANE Select	c.25-5T>C	splice_region intron	N/A	ENSP00000343709.5	Q9Y5X0-1
SNX10	ENST00000396376.5	TSL:1	c.25-5T>C	splice_region intron	N/A	ENSP00000379661.1	Q9Y5X0-1
SNX10	ENST00000446848.6	TSL:1	c.25-5T>C	splice_region intron	N/A	ENSP00000395474.3	Q9Y5X0-1

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00201

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00229

AC:

575

AN:

250650

AF XY:

0.00229

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.00248

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00198

AC:

2886

AN:

1460728

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1402

AN XY:

726704

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33448

American (AMR)

AF:

0.0000448

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39622

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.0140

AC:

741

AN:

52914

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00183

AC:

2039

AN:

1111716

Other (OTH)

AF:

0.00159

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

135

271

406

542

677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.00200

AC:

304

AN:

152318

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

182

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41570

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0139

AC:

148

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00201

AC:

137

AN:

68028

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00174

Hom.:

Bravo

AF:

0.000929

EpiCase

AF:

0.00104

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

SNX10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

2.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.052

dbscSNV1_RF

Benign

0.30

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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