8-75013999-A-G

Position:

• chr8-75013999-A-G

Variant summary

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

The NM_031461.6(CRISPLD1):​c.523A>G​(p.Thr175Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,210 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: 6.8e-7 (0 hom.)
• Consequence: CRISPLD1 NM_031461.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.20

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, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRISPLD1	NM_031461.6	c.523A>G	p.Thr175Ala	missense_variant	5/15	ENST00000262207.9
CRISPLD1	NM_001286778.2	c.-42A>G		5_prime_UTR_variant	4/14
CRISPLD1	NM_001286777.2	c.69-813A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRISPLD1	ENST00000262207.9	c.523A>G	p.Thr175Ala	missense_variant	5/15	1	NM_031461.6	P1
CRISPLD1	ENST00000523524.5	c.-42A>G		5_prime_UTR_variant	4/14	2
CRISPLD1	ENST00000517786.1	c.69-813A>G		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460210 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726456

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.523A>G (p.T175A) alteration is located in exon 5 (coding exon 4) of the CRISPLD1 gene. This alteration results from a A to G substitution at nucleotide position 523, causing the threonine (T) at amino acid position 175 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	0.22
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.37		Gain of sheet (P = 0.0827);
MVP		0.82
MPC		0.65
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.31
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1167817081; hg19: chr8-75926234;