dbSNP rs3087822: CRIPT:c.*667A>G (chr2-46624894-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014171.6(CRIPT):c.*667A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 151,664 control chromosomes in the GnomAD database, including 21,144 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 21144 hom., cov: 30)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

CRIPT
NM_014171.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.932

Publications

42 publications found

Variant links:

Genes affected

CRIPT (HGNC:14312): (CXXC repeat containing interactor of PDZ3 domain) This gene encodes a protein that binds to the PDZ3 peptide recognition domain. The encoded protein may modulates protein interactions with the cytoskeleton. A mutation in this gene resulted in short stature with microcephaly and distinctive facies. [provided by RefSeq, Jun 2014]

CRIPT Gene-Disease associations (from GenCC):

Rothmund-Thomson syndrome, type 3
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

CRIPT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRIPT	NM_014171.6 link	c.*667A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000238892.4	NP_054890.1	Q9P021

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRIPT	ENST00000238892.4 link	c.*667A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_014171.6	ENSP00000238892.3		Q9P021

Frequencies

GnomAD3 genomes

AF:

0.507

AC:

76826

AN:

151544

Hom.:

21101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.721

Gnomad AMI

AF:

0.498

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.473

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.507

AC:

76919

AN:

151662

Hom.:

21144

Cov.:

AF XY:

0.500

AC XY:

37068

AN XY:

74120

show subpopulations

African (AFR)

AF:

0.722

AC:

29773

AN:

41254

American (AMR)

AF:

0.494

AC:

7529

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.510

AC:

1766

AN:

3464

East Asian (EAS)

AF:

0.162

AC:

839

AN:

5188

South Asian (SAS)

AF:

0.477

AC:

2290

AN:

4804

European-Finnish (FIN)

AF:

0.327

AC:

3434

AN:

10494

Middle Eastern (MID)

AF:

0.503

AC:

147

AN:

292

European-Non Finnish (NFE)

AF:

0.437

AC:

29714

AN:

67926

Other (OTH)

AF:

0.467

AC:

975

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1750

3500

5250

7000

8750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

666

1332

1998

2664

3330

<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:

0.469

Hom.:

23539

Bravo

AF:

0.523

Asia WGS

AF:

0.351

AC:

1222

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.28

(source)

DANN

Benign

0.79

PhyloP100

-0.93

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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