Genetic Variant ENST00000612404.4:c.*832_*833insTACGTT (chr5-66156903-A-ATTACGT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The ENST00000612404.4(SREK1):c.*832_*833insTACGTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000203 in 984,484 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 0.0000066 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

SREK1
ENST00000612404.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.503

Publications

2 publications found

Variant links:

Genes affected

SREK1 (HGNC:17882): (splicing regulatory glutamic acid and lysine rich protein 1) This gene encodes a member of a family of serine/arginine-rich (SR) splicing proteins containing RNA recognition motif (RRM) domains. The encoded protein interacts with other SR proteins to modulate splice site selection. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

SREK1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SREK1	NM_001077199.3 link	c.296-2315_296-2314insTACGTT		intron_variant	Intron 2 of 11	ENST00000334121.11	NP_001070667.1	Q8WXA9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SREK1	ENST00000334121.11 link	c.296-2315_296-2314insTACGTT		intron_variant	Intron 2 of 11	2	NM_001077199.3	ENSP00000334538.6		Q8WXA9-2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151550

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000120

AC:

AN:

832934

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

384628

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

15778

American (AMR)

AF:

0.00

AC:

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5150

East Asian (EAS)

AF:

0.00

AC:

AN:

3628

South Asian (SAS)

AF:

0.00

AC:

AN:

16456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1618

European-Non Finnish (NFE)

AF:

0.00000131

AC:

AN:

761760

Other (OTH)

AF:

0.00

AC:

AN:

27284

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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:

0.00000660

AC:

AN:

151550

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73966

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

41108

American (AMR)

AF:

0.0000656

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67924

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

121

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.50

Splicing

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

Publications

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ENST00000612404.4:c.832_833insTACGTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over