chr17-31349086-CTTGTTTGTTTGT-C

Variant names:

• chr17-31349086-CTTGTTTGTTTGT-C
• rs149197458
• NM_001042492.3:c.7190-19_7190-8delGTTTGTTTGTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001042492.3(NF1):​c.7190-19_7190-8delGTTTGTTTGTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00184 in 1,550,904 control chromosomes in the GnomAD database, including 44 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (22 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.75
• 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 -16 ACMG points.

• BP6: Variant 17-31349086-CTTGTTTGTTTGT-C is Benign according to our data. Variant chr17-31349086-CTTGTTTGTTTGT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00942 (1433/152068) while in subpopulation AFR AF = 0.0326 (1349/41436). AF 95% confidence interval is 0.0311. There are 22 homozygotes in GnomAd4. There are 688 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1433 AD 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.7190-19_7190-8delGTTTGTTTGTTT		splice_region intron	N/A	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.7127-19_7127-8delGTTTGTTTGTTT		splice_region intron	N/A	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.7190-33_7190-22delTTGTTTGTTTGT		intron	N/A	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.7127-33_7127-22delTTGTTTGTTTGT		intron	N/A	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.*2355-33_*2355-22delTTGTTTGTTTGT		intron	N/A	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes AF: 0.00940 AC: 1429 AN: 151954 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.00253 AC: 392 AN: 154686 AF XY: 0.00176

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00102 AC: 1426 AN: 1398836 Hom.: 22 AF XY: 0.000864 AC XY: 597 AN XY: 690818

African (AFR) AF: 0.0319 AC: 1010 AN: 31622

American (AMR) AF: 0.00217 AC: 78 AN: 36012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25190

East Asian (EAS) AF: 0.00 AC: 0 AN: 36008

South Asian (SAS) AF: 0.000138 AC: 11 AN: 79654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47630

Middle Eastern (MID) AF: 0.00406 AC: 23 AN: 5662

European-Non Finnish (NFE) AF: 0.000140 AC: 151 AN: 1079024

Other (OTH) AF: 0.00264 AC: 153 AN: 58034

GnomAD4 genome AF: 0.00942 AC: 1433 AN: 152068 Hom.: 22 Cov.: 32 AF XY: 0.00925 AC XY: 688 AN XY: 74340

African (AFR) AF: 0.0326 AC: 1349 AN: 41436

American (AMR) AF: 0.00360 AC: 55 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67988

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.000336 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Neurofibromatosis, type 1 (2)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs149197458; hg19: chr17-29676104;