rs587782218

Variant names:

• chr17-31232069-T-A
• rs587782218
• NM_001042492.3:c.3198-4T>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31232069-T-A
• chr17-31232069-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001042492.3(NF1):​c.3198-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,161,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005702
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.293

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-4T>A		splice_region_variant, intron_variant	Intron 24 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3198-4T>A		splice_region_variant, intron_variant	Intron 24 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3198-4T>A		splice_region_variant, intron_variant	Intron 24 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1161258 Hom.: 0 Cov.: 20 AF XY: 0.00000344 AC XY: 2 AN XY: 581726

Gnomad4 AFR exome AF: 0.0000406 AC: 1 AN: 24616

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 30344

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 22380

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 36184

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 67750

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 48578

Gnomad4 NFE exome AF: 0.00000114 AC: 1 AN: 879180

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 48822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.44
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0020
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: rs587782218; hg19: chr17-29559087;