dbSNP rs762286966: CRISP1:p.Ala75Thr (chr6-49848272-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001131.3(CRISP1):c.223G>A(p.Ala75Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,605,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CRISP1
NM_001131.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

Publications

0 publications found

Variant links:

Genes affected

CRISP1 (HGNC:304): (cysteine rich secretory protein 1) Fertilization consists of a sequence of specific cell-cell interactions culminating in the fusion of the sperm and egg plasma membranes. Recognition, binding, and fusion occur through the interaction of complementary molecules that are localized to specific domains of the sperm and egg plasma membranes. In the sperm, the postacrosomal region or equatorial segment is involved in sperm-egg plasma membrane fusion. The protein encoded by this gene is a member of the cysteine-rich secretory protein (CRISP) family. It is expressed in the epididymis, is secreted into the epididymal lumen, and binds to the postacrosomal region of the sperm head, where it plays a role in sperm-egg fusion. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

CRISP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRISP1	NM_001131.3	MANE Select	c.223G>A	p.Ala75Thr	missense	Exon 4 of 8	NP_001122.2
CRISP1	NM_001205220.2		c.223G>A	p.Ala75Thr	missense	Exon 4 of 8	NP_001192149.1	P54107-1
CRISP1	NM_170609.2		c.223G>A	p.Ala75Thr	missense	Exon 4 of 7	NP_733758.1	P54107-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRISP1	ENST00000335847.9	TSL:1 MANE Select	c.223G>A	p.Ala75Thr	missense	Exon 4 of 8	ENSP00000338276.4	P54107-1
CRISP1	ENST00000505118.1	TSL:1	c.223G>A	p.Ala75Thr	missense	Exon 4 of 8	ENSP00000427589.1	P54107-1
CRISP1	ENST00000507853.5	TSL:1	c.223G>A	p.Ala75Thr	missense	Exon 4 of 7	ENSP00000425020.1	P54107-2

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

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

GnomAD2 exomes

AF:

0.0000407

AC:

AN:

245900

AF XY:

0.0000451

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00101

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:

0.0000261

AC:

AN:

1454360

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

723442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33046

American (AMR)

AF:

0.00

AC:

AN:

43680

Ashkenazi Jewish (ASJ)

AF:

0.000810

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39424

South Asian (SAS)

AF:

0.00

AC:

AN:

84752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53006

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000812

AC:

AN:

1108742

Other (OTH)

AF:

0.000117

AC:

AN:

60050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

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:

0.0000133

AC:

AN:

150856

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73524

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41016

American (AMR)

AF:

0.00

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67840

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000135

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.80

M_CAP

Benign

0.010

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

4.3

PhyloP100

3.5

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.81

MutPred

0.91

Gain of phosphorylation at A75 (P = 0.0567)

MVP

0.45

MPC

0.10

ClinPred

1.0

GERP RS

4.8

Varity_R

0.67

gMVP

0.61

Mutation Taster

=60/40

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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