Genetic Variant SLC9C1:c.3365-9_3365-7dupTTT (chr3-112155055-T-TAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_183061.3(SLC9C1):c.3365-9_3365-7dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,399,430 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000048 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0023 ( 0 hom. )

Consequence

SLC9C1
NM_183061.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.97

Publications

6 publications found

Variant links:

Genes affected

SLC9C1 (HGNC:31401): (solute carrier family 9 member C1) Predicted to enable potassium:proton antiporter activity and sodium:proton antiporter activity. Predicted to be involved in potassium ion transmembrane transport; regulation of intracellular pH; and sodium ion import across plasma membrane. Predicted to act upstream of or within flagellated sperm motility. Predicted to be located in motile cilium. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC9C1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the SAS (0.00889) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183061.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC9C1	NM_183061.3	MANE Select	c.3365-9_3365-7dupTTT	splice_region intron	N/A	NP_898884.1	Q4G0N8-1
SLC9C1	NM_001320531.2		c.3221-9_3221-7dupTTT	splice_region intron	N/A	NP_001307460.1	Q4G0N8-2
SLC9C1	NR_135297.2		n.2635-9_2635-7dupTTT	splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC9C1	ENST00000305815.10	TSL:2 MANE Select	c.3365-7_3365-6insTTT	splice_region intron	N/A	ENSP00000306627.5	Q4G0N8-1
SLC9C1	ENST00000487372.5	TSL:1	c.3221-7_3221-6insTTT	splice_region intron	N/A	ENSP00000420688.1	Q4G0N8-2
SLC9C1	ENST00000471295.1	TSL:5	n.1694-7_1694-6insTTT	splice_region intron	N/A	ENSP00000418371.1	F8WCJ0

Frequencies

GnomAD3 genomes

AF:

0.0000482

AC:

AN:

145358

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000506

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000433

Gnomad FIN

AF:

0.000113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000302

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00370

AC:

594

AN:

160354

AF XY:

0.00345

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00488

Gnomad ASJ exome

AF:

0.00252

Gnomad EAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.00192

Gnomad NFE exome

AF:

0.00234

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00226

AC:

2834

AN:

1254072

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1529

AN XY:

625808

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00124

AC:

AN:

28280

American (AMR)

AF:

0.00407

AC:

130

AN:

31918

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

22680

East Asian (EAS)

AF:

0.00610

AC:

212

AN:

34744

South Asian (SAS)

AF:

0.00948

AC:

671

AN:

70774

European-Finnish (FIN)

AF:

0.00164

AC:

AN:

40238

Middle Eastern (MID)

AF:

0.00190

AC:

AN:

4728

European-Non Finnish (NFE)

AF:

0.00161

AC:

1555

AN:

968574

Other (OTH)

AF:

0.00226

AC:

118

AN:

52136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.265

Heterozygous variant carriers

333

666

998

1331

1664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

180

240

300

<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:

0.0000482

AC:

AN:

145358

Hom.:

Cov.:

AF XY:

0.0000568

AC XY:

AN XY:

70400

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000506

AC:

AN:

39510

American (AMR)

AF:

0.00

AC:

AN:

14508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3390

East Asian (EAS)

AF:

0.00

AC:

AN:

5034

South Asian (SAS)

AF:

0.000433

AC:

AN:

4614

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

8838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.0000302

AC:

AN:

66300

Other (OTH)

AF:

0.00

AC:

AN:

1970

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00353511), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.346

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:

0.00

Hom.:

903

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-4.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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3-112155055-TAAAA-TAAAAAAA

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