8-75013990-G-A

Variant names:

• chr8-75013990-G-A
• rs200705853
• NM_031461.6:c.514G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001286778.2(CRISPLD1):​c.-51G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000814 in 1,608,682 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: CRISPLD1 NM_001286778.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.87

Genes affected

CRISPLD1 (HGNC:18206): (cysteine rich secretory protein LCCL domain containing 1) Involved in face morphogenesis. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRISPLD1	NM_031461.6	c.514G>A	p.Val172Met	missense_variant	Exon 5 of 15	ENST00000262207.9	NP_113649.1
CRISPLD1	NM_001286778.2	c.-51G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 14		NP_001273707.1
CRISPLD1	NM_001286778.2	c.-51G>A		5_prime_UTR_variant	Exon 4 of 14		NP_001273707.1
CRISPLD1	NM_001286777.2	c.69-822G>A		intron_variant	Intron 3 of 12		NP_001273706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRISPLD1	ENST00000262207.9	c.514G>A	p.Val172Met	missense_variant	Exon 5 of 15	1	NM_031461.6	ENSP00000262207.4
CRISPLD1	ENST00000523524	c.-51G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 14	2		ENSP00000430105.1
CRISPLD1	ENST00000523524	c.-51G>A		5_prime_UTR_variant	Exon 4 of 14	2		ENSP00000430105.1
CRISPLD1	ENST00000517786.1	c.69-822G>A		intron_variant	Intron 3 of 12	2		ENSP00000429746.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151932 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000957 AC: 24 AN: 250850 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000879 AC: 128 AN: 1456750 Hom.: 0 Cov.: 29 AF XY: 0.000106 AC XY: 77 AN XY: 724936

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000546

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000641

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151932 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74182

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000783 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514G>A (p.V172M) alteration is located in exon 5 (coding exon 4) of the CRISPLD1 gene. This alteration results from a G to A substitution at nucleotide position 514, causing the valine (V) at amino acid position 172 to be replaced by a methionine (M). 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	0.96
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.58		Loss of catalytic residue at V172 (P = 0.0024);
MVP		0.71
MPC		0.75
ClinPred		0.65	D
GERP RS		4.8
Varity_R		0.42
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200705853; hg19: chr8-75926225; COSMIC: COSV51547514; COSMIC: COSV51547514;