17-31155970-CTTT-CTT

Variant names:

• chr17-31155970-CT-C
• rs551568608
• NM_001042492.3:c.61-4delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001042492.3(NF1):​c.61-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,531,678 control chromosomes in the GnomAD database, including 8 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.175
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP6: Variant 17-31155970-CT-C is Benign according to our data. Variant chr17-31155970-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 322566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 297 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.61-4delT		splice_region intron	N/A	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.61-4delT		splice_region intron	N/A	NP_000258.1
	NF1	NM_001128147.3		c.61-4delT		splice_region intron	N/A	NP_001121619.1	P21359-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.61-12delT		intron	N/A	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.61-12delT		intron	N/A	ENSP00000348498.3	P21359-2
	NF1	ENST00000431387.8	TSL:1	c.61-12delT		intron	N/A	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 297 AN: 145224 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000274

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.000503

GnomAD2 exomes AF: 0.00327 AC: 575 AN: 175788 AF XY: 0.00307

Gnomad AFR exome AF: 0.000596

Gnomad AMR exome AF: 0.000217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000158

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00221 AC: 3062 AN: 1386372 Hom.: 6 Cov.: 33 AF XY: 0.00213 AC XY: 1467 AN XY: 689360

African (AFR) AF: 0.000497 AC: 15 AN: 30192

American (AMR) AF: 0.000193 AC: 7 AN: 36228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24256

East Asian (EAS) AF: 0.0000546 AC: 2 AN: 36648

South Asian (SAS) AF: 0.000151 AC: 12 AN: 79586

European-Finnish (FIN) AF: 0.0116 AC: 556 AN: 48012

Middle Eastern (MID) AF: 0.000373 AC: 2 AN: 5368

European-Non Finnish (NFE) AF: 0.00222 AC: 2377 AN: 1069466

Other (OTH) AF: 0.00161 AC: 91 AN: 56616

GnomAD4 genome AF: 0.00204 AC: 297 AN: 145306 Hom.: 2 Cov.: 31 AF XY: 0.00235 AC XY: 166 AN XY: 70642

African (AFR) AF: 0.000583 AC: 23 AN: 39466

American (AMR) AF: 0.000274 AC: 4 AN: 14622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5002

South Asian (SAS) AF: 0.00 AC: 0 AN: 4588

European-Finnish (FIN) AF: 0.0134 AC: 122 AN: 9088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00223 AC: 147 AN: 65934

Other (OTH) AF: 0.000498 AC: 1 AN: 2008

Alfa AF: 0.00124 Hom.: 1

Bravo AF: 0.00122

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Neurofibromatosis, type 1 (5)
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Café-au-lait macules with pulmonary stenosis (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
-	-	1	Neurofibromatosis-Noonan syndrome (1)
-	-	1	Neurofibromatosis, familial spinal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs551568608; hg19: chr17-29482988; COSMIC: COSV62198210; COSMIC: COSV62198210;