chr17-31258376-C-T

Variant names:

• chr17-31258376-C-T
• rs864622406
• NM_001042492.3:c.4206C>T
• NF1 p.Ile1402Ile

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_ModerateBP6_StrongBP7

The NM_001042492.3(NF1):c.4206C>T (p.Ile1402Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000157 (AC=23) in the gnomAD database across 1,461,676 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000109. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.182
• Publications: 3 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), PanelApp Australia, ClinGen, 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000109 — very rare for AD/XL gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00122) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NF1 NM_001042492.3	MANE Select	c.4206C>T p.Ile1402Ile	synonymous	Exon 32 of 58	Prot: NP_001035957.1 UniProt:
	NF1 NM_000267.4		c.4143C>T p.Ile1381Ile	synonymous	Exon 31 of 57	Prot: NP_000258.1 UniProt:

NF1 NM_001042492.3

MANE Select

HGVSc / HGVSpc.4206C>Tp.Ile1402Ile

Exon rankExon 32 of 58

synonymous

Prot: NP_001035957.1UniProt: P21359-1

NF1 NM_000267.4

HGVSc / HGVSpc.4143C>Tp.Ile1381Ile

Exon rankExon 31 of 57

synonymous

Prot: NP_000258.1UniProt: P21359-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NF1 ENST00000358273.9	TSL:1MANE Select	c.4206C>T p.Ile1402Ile	synonymous	Exon 32 of 58	Prot: ENSP00000351015.4 UniProt:
	NF1 ENST00000356175.7	TSL:1	c.4143C>T p.Ile1381Ile	synonymous	Exon 31 of 57	Prot: ENSP00000348498.3 UniProt:
	NF1 ENST00000579081.6	TSL:1	n.4143C>T	non_coding_transcript_exon	Exon 31 of 58	Prot: ENSP00000462408.2 UniProt:

NF1 ENST00000358273.9

TSL:1MANE Select

HGVSc / HGVSpc.4206C>Tp.Ile1402Ile

Exon rankExon 32 of 58

synonymous

Prot: ENSP00000351015.4UniProt: P21359-1

NF1 ENST00000356175.7

TSL:1

HGVSc / HGVSpc.4143C>Tp.Ile1381Ile

Exon rankExon 31 of 57

synonymous

Prot: ENSP00000348498.3UniProt: P21359-2

NF1 ENST00000579081.6

TSL:1

HGVSc / HGVSpn.4143C>T

Exon rankExon 31 of 58

non_coding_transcript_exon

Prot: ENSP00000462408.2UniProt: J3KSB5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251242	Cov:
GnomAD4 exome	AF: 0.0000157	AC:23	Hom:0	AN:1461676	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:121886	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9622	0.0000959 *	1	10426
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.0000150	1	66884
SCHEMA(Schizophrenia)	0.0000147	1	67858	0.0000300	4	133320

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Neurofibromatosis, type 1 (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.77
GPN-Star LLR	N/A	-3.5
GPN-Star score	N/A	3.5
PhyloP100	Benign	0.18
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs864622406;

hg19: chr17-29585394;

COSMIC: COSV62195111;

COSMIC: COSV62195111;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar