17-31358473-C-T

Variant names:

• chr17-31358473-C-T
• rs754359027
• NM_001042492.3:c.7971-7C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001042492.3(NF1):​c.7971-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003180
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.28
• Publications: 1 publications found

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]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-31358473-C-T is Benign according to our data. Variant chr17-31358473-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 767034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.7971-7C>T		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.7908-7C>T		splice_region intron	N/A	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.7971-7C>T		splice_region intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.7908-7C>T		splice_region intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*3136-7C>T		splice_region intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149960 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000266 AC: 64 AN: 240168 AF XY: 0.000185

Gnomad AFR exome AF: 0.000505

Gnomad AMR exome AF: 0.0000621

Gnomad ASJ exome AF: 0.000311

Gnomad EAS exome AF: 0.000230

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000349

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000449 AC: 65 AN: 1448756 Hom.: 0 Cov.: 31 AF XY: 0.0000389 AC XY: 28 AN XY: 720638

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000185 AC: 6 AN: 32374

American (AMR) AF: 0.000218 AC: 9 AN: 41318

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 4 AN: 25680

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39598

South Asian (SAS) AF: 0.0000716 AC: 6 AN: 83822

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1107554

Other (OTH) AF: 0.000101 AC: 6 AN: 59692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 149960 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73048

African (AFR) AF: 0.00 AC: 0 AN: 40848

American (AMR) AF: 0.00 AC: 0 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67366

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00242 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.4
DANN	Benign	0.50
PhyloP100		1.3
PromoterAI		-0.046	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754359027; hg19: chr17-29685491;