6-49848260-A-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001131.3(CRISP1):c.235T>G(p.Ser79Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,608,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CRISP1
NM_001131.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.154

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034055293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRISP1	NM_001131.3 link	c.235T>G	p.Ser79Ala	missense_variant	Exon 4 of 8	ENST00000335847.9	NP_001122.2	P54107-1A0A0K0K1I1
CRISP1	NM_001205220.2 link	c.235T>G	p.Ser79Ala	missense_variant	Exon 4 of 8		NP_001192149.1	P54107-1A0A0K0K1I1
CRISP1	NM_170609.2 link	c.235T>G	p.Ser79Ala	missense_variant	Exon 4 of 7		NP_733758.1	P54107-2
CRISP1	XM_017010320.3 link	c.-547T>G		upstream_gene_variant			XP_016865809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRISP1	ENST00000335847.9 link	c.235T>G	p.Ser79Ala	missense_variant	Exon 4 of 8	1	NM_001131.3	ENSP00000338276.4	P54107-1
CRISP1	ENST00000505118.1 link	c.235T>G	p.Ser79Ala	missense_variant	Exon 4 of 8	1		ENSP00000427589.1	P54107-1
CRISP1	ENST00000507853.5 link	c.235T>G	p.Ser79Ala	missense_variant	Exon 4 of 7	1		ENSP00000425020.1	P54107-2
CRISP1	ENST00000329411.9 link	c.235T>G	p.Ser79Ala	missense_variant	Exon 3 of 6	5		ENSP00000331317.5	P54107-2

Frequencies

GnomAD3 genomes

AF:

0.0000922

AC:

AN:

151860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247996

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134190

show subpopulations

Gnomad AFR exome

AF:

0.000310

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000480

AC:

AN:

1456996

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724776

show subpopulations

Gnomad4 AFR exome

AF:

0.000211

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000921

AC:

AN:

151978

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000101

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.235T>G (p.S79A) alteration is located in exon 4 (coding exon 3) of the CRISP1 gene. This alteration results from a T to G substitution at nucleotide position 235, causing the serine (S) at amino acid position 79 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.58

DANN

Benign

0.21

DEOGEN2

Benign

0.060

.;T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.29

.;.;T;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.034

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.97

N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

1.1

N;N;N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.047

B;B;B;B

Vest4

0.26

MVP

0.14

MPC

0.014

ClinPred

0.020

GERP RS

-4.4

Varity_R

0.059

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over