17-31095069-T-TC

Variant names:

• chr17-31095069-T-TC
• rs886052788
• NM_001042492.3:c.-237dupC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001042492.3(NF1):​c.-237dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: 0.473
• 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]

MIR4733HG (HGNC:55332): (MIR4733 host gene)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.-237dupC		5_prime_UTR_variant	Exon 1 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.-237dupC		5_prime_UTR_variant	Exon 1 of 57		NP_000258.1
NF1	NM_001128147.3	c.-237dupC		5_prime_UTR_variant	Exon 1 of 15		NP_001121619.1
MIR4733HG	NR_186435.1	n.264+157dupG		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.-237dupC		5_prime_UTR_variant	Exon 1 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 40194 Hom.: 0 Cov.: 26

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

GnomAD4 exome AF: 0.00164 AC: 119 AN: 72680 Hom.: 0 Cov.: 0 AF XY: 0.00207 AC XY: 80 AN XY: 38658

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

African (AFR) AF: 0.000579 AC: 1 AN: 1728

American (AMR) AF: 0.000433 AC: 1 AN: 2312

Ashkenazi Jewish (ASJ) AF: 0.000423 AC: 1 AN: 2366

East Asian (EAS) AF: 0.000211 AC: 1 AN: 4736

South Asian (SAS) AF: 0.00577 AC: 44 AN: 7632

European-Finnish (FIN) AF: 0.000954 AC: 5 AN: 5240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 332

European-Non Finnish (NFE) AF: 0.00143 AC: 63 AN: 44102

Other (OTH) AF: 0.000709 AC: 3 AN: 4232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), 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: 40228 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 19762

African (AFR) AF: 0.00 AC: 0 AN: 10438

American (AMR) AF: 0.00 AC: 0 AN: 4104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 996

East Asian (EAS) AF: 0.00 AC: 0 AN: 1618

South Asian (SAS) AF: 0.00 AC: 0 AN: 1256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 74

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 18666

Other (OTH) AF: 0.00 AC: 0 AN: 572

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, familial spinal Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis-Noonan syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Café-au-lait macules with pulmonary stenosis Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
Mutation Taster		=258/42	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: rs886052788; hg19: chr17-29422087;