Genetic Variant SLC24A5:p.Tyr191LeufsTer3 (chr15-48134963-T-TATTA) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_205850.3(SLC24A5):c.571_572insTAAT(p.Tyr191LeufsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as association (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SLC24A5
NM_205850.3 frameshift

Scores

Not classified

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 1.80

Publications

0 publications found

Variant links:

Genes affected

SLC24A5 (HGNC:20611): (solute carrier family 24 member 5) This gene is a member of the potassium-dependent sodium/calcium exchanger family and encodes an intracellular membrane protein with 2 large hydrophilic loops and 2 sets of multiple transmembrane-spanning segments. Sequence variation in this gene has been associated with differences in skin pigmentation. [provided by RefSeq, Jul 2008]

SLC24A5 links:

MYEF2 (HGNC:17940): (myelin expression factor 2) Enables RNA binding activity. Involved in myotube differentiation and neuron differentiation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MYEF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_205850.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC24A5	NM_205850.3	MANE Select	c.571_572insTAAT	p.Tyr191LeufsTer3	frameshift	Exon 5 of 9	NP_995322.1
MYEF2	NM_016132.5	MANE Select	c.7944_7945insTAAT		3_prime_UTR	Exon 17 of 17	NP_057216.3
MYEF2	NM_001301210.2		c.7944_7945insTAAT		3_prime_UTR	Exon 16 of 16	NP_001288139.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC24A5	ENST00000341459.8	TSL:1 MANE Select	c.571_572insTAAT	p.Tyr191LeufsTer3	frameshift	Exon 5 of 9	ENSP00000341550.3
SLC24A5	ENST00000449382.2	TSL:1	c.391_392insTAAT	p.Tyr131LeufsTer3	frameshift	Exon 4 of 8	ENSP00000389966.2
MYEF2	ENST00000324324.12	TSL:1 MANE Select	c.7944_7945insTAAT		3_prime_UTR	Exon 17 of 17	ENSP00000316950.7

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250504

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1457918

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724894

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.0000816

AC:

AN:

85758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109100

Other (OTH)

AF:

0.0000664

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Skin/hair/eye pigmentation, variation in, 4

Other:1

Dec 15, 2012

OMIM

Significance:association

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=5/195

disease causing (fs/PTC)

(source)

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over