10-101770141-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAA

Variant names:

• chr10-101770141-T-TAA
• rs11322844
• NM_033163.5:c.*186_*187dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_033163.5(FGF8):​c.*186_*187dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.032 (74 hom., cov: 0)
  • Exomes 𝑓: 0.018 (0 hom.)
• Consequence: FGF8 NM_033163.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• Publications: 1 publications found

Genes affected

FGF8 (HGNC:3686): (fibroblast growth factor 8) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members 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 known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogensis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs revealed roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants. [provided by RefSeq, Jul 2008]

FGF8 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 6 with or without anosmia

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000308881 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0322 (3888/120620) while in subpopulation NFE AF = 0.0415 (2428/58498). AF 95% confidence interval is 0.0401. There are 74 homozygotes in GnomAd4. There are 1707 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 74 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF8	NM_033163.5	c.*186_*187dupTT		3_prime_UTR_variant	Exon 6 of 6	ENST00000320185.7	NP_149353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF8	ENST00000320185.7	c.*186_*187dupTT		3_prime_UTR_variant	Exon 6 of 6	1	NM_033163.5	ENSP00000321797.2

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 3887 AN: 120636 Hom.: 73 Cov.: 0

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.0183

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00529

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0266

GnomAD4 exome AF: 0.0183 AC: 4894 AN: 267786 Hom.: 0 Cov.: 0 AF XY: 0.0183 AC XY: 2519 AN XY: 137466

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

African (AFR) AF: 0.0300 AC: 219 AN: 7312

American (AMR) AF: 0.0125 AC: 121 AN: 9666

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 92 AN: 8940

East Asian (EAS) AF: 0.0107 AC: 228 AN: 21370

South Asian (SAS) AF: 0.0118 AC: 177 AN: 15036

European-Finnish (FIN) AF: 0.0150 AC: 291 AN: 19458

Middle Eastern (MID) AF: 0.0122 AC: 15 AN: 1228

European-Non Finnish (NFE) AF: 0.0204 AC: 3437 AN: 168400

Other (OTH) AF: 0.0192 AC: 314 AN: 16376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0322 AC: 3888 AN: 120620 Hom.: 74 Cov.: 0 AF XY: 0.0299 AC XY: 1707 AN XY: 57124

African (AFR) AF: 0.0342 AC: 1081 AN: 31588

American (AMR) AF: 0.0146 AC: 176 AN: 12092

Ashkenazi Jewish (ASJ) AF: 0.00529 AC: 16 AN: 3022

East Asian (EAS) AF: 0.00 AC: 0 AN: 4216

South Asian (SAS) AF: 0.00835 AC: 31 AN: 3714

European-Finnish (FIN) AF: 0.0203 AC: 97 AN: 4782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.0415 AC: 2428 AN: 58498

Other (OTH) AF: 0.0265 AC: 44 AN: 1662

Alfa AF: 0.0151 Hom.: 142

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11

Splicing

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

Other links and lift over

dbSNP: rs11322844; hg19: chr10-103529898;