6-49838440-A-T

Variant names:

• chr6-49838440-A-T
• rs1770875533
• NM_001131.3:c.619T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001131.3(CRISP1):​c.619T>A​(p.Cys207Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,642 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRISP1 NM_001131.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.35

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRISP1	NM_001131.3	c.619T>A	p.Cys207Ser	missense_variant	Exon 7 of 8	ENST00000335847.9	NP_001122.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRISP1	ENST00000335847.9	c.619T>A	p.Cys207Ser	missense_variant	Exon 7 of 8	1	NM_001131.3	ENSP00000338276.4
CRISP1	ENST00000505118.1	c.619T>A	p.Cys207Ser	missense_variant	Exon 7 of 8	1		ENSP00000427589.1
CRISP1	ENST00000507853.5	c.533+2458T>A		intron_variant	Intron 6 of 6	1		ENSP00000425020.1
CRISP1	ENST00000329411.9	c.533+2458T>A		intron_variant	Intron 5 of 5	5		ENSP00000331317.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456642 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724890

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.619T>A (p.C207S) alteration is located in exon 7 (coding exon 6) of the CRISP1 gene. This alteration results from a T to A substitution at nucleotide position 619, causing the cysteine (C) at amino acid position 207 to be replaced by a serine (S). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.0070	T
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-9.2	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.83		Gain of glycosylation at C207 (P = 0.0306);Gain of glycosylation at C207 (P = 0.0306);
MVP		0.49
MPC		0.11
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.89

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

Other links and lift over

dbSNP: rs1770875533; hg19: chr6-49806153;