6-49848245-T-C

Variant names:

• chr6-49848245-T-C
• NM_001131.3:c.250A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001131.3(CRISP1):​c.250A>G​(p.Met84Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,766 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: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CRISP1 NM_001131.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.783

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085226625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRISP1	NM_001131.3	c.250A>G	p.Met84Val	missense_variant	Exon 4 of 8	ENST00000335847.9	NP_001122.2
CRISP1	NM_001205220.2	c.250A>G	p.Met84Val	missense_variant	Exon 4 of 8		NP_001192149.1
CRISP1	NM_170609.2	c.250A>G	p.Met84Val	missense_variant	Exon 4 of 7		NP_733758.1
CRISP1	XM_017010320.3	c.-532A>G		upstream_gene_variant			XP_016865809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRISP1	ENST00000335847.9	c.250A>G	p.Met84Val	missense_variant	Exon 4 of 8	1	NM_001131.3	ENSP00000338276.4
CRISP1	ENST00000505118.1	c.250A>G	p.Met84Val	missense_variant	Exon 4 of 8	1		ENSP00000427589.1
CRISP1	ENST00000507853.5	c.250A>G	p.Met84Val	missense_variant	Exon 4 of 7	1		ENSP00000425020.1
CRISP1	ENST00000329411.9	c.250A>G	p.Met84Val	missense_variant	Exon 3 of 6	5		ENSP00000331317.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455766 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724246

Gnomad4 AFR exome AF: 0.00

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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.250A>G (p.M84V) alteration is located in exon 4 (coding exon 3) of the CRISP1 gene. This alteration results from a A to G substitution at nucleotide position 250, causing the methionine (M) at amino acid position 84 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.069
DANN	Benign	0.33
DEOGEN2	Benign	0.061	.;T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.38	.;.;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.79	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.84	N;N;N;N
REVEL	Benign	0.022
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.0060	B;B;B;B
Vest4		0.14
MutPred		0.63		Gain of ubiquitination at K80 (P = 0.0544);Gain of ubiquitination at K80 (P = 0.0544);Gain of ubiquitination at K80 (P = 0.0544);Gain of ubiquitination at K80 (P = 0.0544);
MVP		0.061
MPC		0.015
ClinPred		0.12	T
GERP RS		-9.5
Varity_R		0.066
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-49815958;