17-30803931-C-T

Variant names:

• chr17-30803931-C-T
• rs1378918533
• NM_015986.4:c.307G>A

Variant summary

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

The NM_015986.4(CRLF3):​c.307G>A​(p.Val103Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: CRLF3 NM_015986.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69

Genes affected

CRLF3 (HGNC:17177): (cytokine receptor like factor 3) This gene encodes a cytokine receptor-like factor that may negatively regulate cell cycle progression at the G0/G1 phase. Studies of the related rat protein suggest that it may regulate neuronal morphology and synaptic vesicle biogenesis. This gene is one of several genes located in the neurofibromatosis type I tumor suppressor region on the q arm of chromosome 17, a region that is subject to microdeletions, duplications, chromosomal breaks and rearrangements. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 2 and 5. [provided by RefSeq, Aug 2012]

ENSG00000276250 (HGNC:):

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=0.25606018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF3	NM_015986.4	c.307G>A	p.Val103Ile	missense_variant	Exon 2 of 8	ENST00000324238.7	NP_057070.3
CRLF3	NR_073118.2	n.171-6533G>A		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF3	ENST00000324238.7	c.307G>A	p.Val103Ile	missense_variant	Exon 2 of 8	1	NM_015986.4	ENSP00000318804.6
CRLF3	ENST00000583805.1	n.590G>A		non_coding_transcript_exon_variant	Exon 2 of 2	4
ENSG00000276250	ENST00000621598.1	n.278C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
CRLF3	ENST00000578692.1	n.130-6533G>A		intron_variant	Intron 1 of 6	2		ENSP00000462643.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726262

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.307G>A (p.V103I) alteration is located in exon 2 (coding exon 2) of the CRLF3 gene. This alteration results from a G to A substitution at nucleotide position 307, causing the valine (V) at amino acid position 103 to be replaced by an isoleucine (I). 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	0.080
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.16	N
REVEL	Uncertain	0.34
Sift	Benign	0.62	T
Sift4G	Benign	0.25	T
Polyphen		0.73	P
Vest4		0.52
MutPred		0.19		Gain of helix (P = 0.0854);
MVP		0.53
MPC		0.91
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.066
gMVP		0.27

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: rs1378918533; hg19: chr17-29130949;