8-22043238-C-T

Variant names:

• chr8-22043238-C-T
• rs3176271
• NM_003867.4:c.72+57C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003867.4(FGF17):​c.72+57C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,553,208 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (23 hom.)
• Consequence: FGF17 NM_003867.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58
• Publications: 1 publications found

Genes affected

FGF17 (HGNC:3673): (fibroblast growth factor 17) This gene encodes a member of the fibroblast growth factor (FGF) family. Member of the FGF family possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes including embryonic development cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein is expressed during embryogenesis and in the adult cerebellum and cortex and may be essential for vascular growth and normal brain development. Mutations in this gene are the cause of hypogonadotropic hypogonadism 20 with or without anosmia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

FGF17 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 20 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-22043238-C-T is Benign according to our data. Variant chr8-22043238-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1220197.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 = 0.0094 (1432/152282) while in subpopulation AFR AF = 0.0322 (1340/41552). AF 95% confidence interval is 0.0308. There are 14 homozygotes in GnomAd4. There are 676 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1432 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003867.4. 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
	FGF17	NM_003867.4	MANE Select	c.72+57C>T		intron	N/A	NP_003858.1	O60258-1
	FGF17	NM_001304478.1		c.72+57C>T		intron	N/A	NP_001291407.1	O60258-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF17	ENST00000359441.4	TSL:1 MANE Select	c.72+57C>T		intron	N/A	ENSP00000352414.3	O60258-1
	FGF17	ENST00000518533.5	TSL:1	c.72+57C>T		intron	N/A	ENSP00000431041.1	O60258-2

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1432 AN: 152164 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0323

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00767

GnomAD4 exome AF: 0.00119 AC: 1669 AN: 1400926 Hom.: 23 AF XY: 0.00103 AC XY: 724 AN XY: 699664

African (AFR) AF: 0.0338 AC: 1096 AN: 32432

American (AMR) AF: 0.00250 AC: 110 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25598

East Asian (EAS) AF: 0.000178 AC: 7 AN: 39376

South Asian (SAS) AF: 0.000178 AC: 15 AN: 84166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48004

Middle Eastern (MID) AF: 0.00495 AC: 28 AN: 5652

European-Non Finnish (NFE) AF: 0.000249 AC: 265 AN: 1063200

Other (OTH) AF: 0.00253 AC: 148 AN: 58460

GnomAD4 genome AF: 0.00940 AC: 1432 AN: 152282 Hom.: 14 Cov.: 33 AF XY: 0.00908 AC XY: 676 AN XY: 74462

African (AFR) AF: 0.0322 AC: 1340 AN: 41552

American (AMR) AF: 0.00307 AC: 47 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68022

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.00613 Hom.: 1

Bravo AF: 0.0113

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

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	-0.80
CADD	Benign	0.076
DANN	Benign	0.69
PhyloP100		-2.6
PromoterAI		0.019	Neutral
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: rs3176271; hg19: chr8-21900749;