10-101770141-TAA-T

Variant names:

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

Variant summary

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

The NM_033163.5(FGF8):​c.*186_*187delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 382,198 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 0)
  • Exomes 𝑓: 0.11 (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 afr. GnomAd4 allele frequency = 0.00313 (378/120744) while in subpopulation AFR AF = 0.0068 (215/31612). AF 95% confidence interval is 0.00606. There are 2 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 377 AN: 120762 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00166

Gnomad EAS AF: 0.00142

Gnomad SAS AF: 0.00240

Gnomad FIN AF: 0.00146

Gnomad MID AF: 0.0123

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00121

GnomAD4 exome AF: 0.110 AC: 28647 AN: 261454 Hom.: 0 AF XY: 0.111 AC XY: 14898 AN XY: 134426

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

African (AFR) AF: 0.0767 AC: 548 AN: 7148

American (AMR) AF: 0.130 AC: 1213 AN: 9356

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 872 AN: 8662

East Asian (EAS) AF: 0.105 AC: 2154 AN: 20606

South Asian (SAS) AF: 0.146 AC: 2159 AN: 14776

European-Finnish (FIN) AF: 0.123 AC: 2334 AN: 19012

Middle Eastern (MID) AF: 0.112 AC: 131 AN: 1168

European-Non Finnish (NFE) AF: 0.106 AC: 17479 AN: 164746

Other (OTH) AF: 0.110 AC: 1757 AN: 15980

⚠️ 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: 0.00313 AC: 378 AN: 120744 Hom.: 2 Cov.: 0 AF XY: 0.00344 AC XY: 197 AN XY: 57194

African (AFR) AF: 0.00680 AC: 215 AN: 31612

American (AMR) AF: 0.00165 AC: 20 AN: 12092

Ashkenazi Jewish (ASJ) AF: 0.00166 AC: 5 AN: 3020

East Asian (EAS) AF: 0.00142 AC: 6 AN: 4218

South Asian (SAS) AF: 0.00216 AC: 8 AN: 3712

European-Finnish (FIN) AF: 0.00146 AC: 7 AN: 4796

Middle Eastern (MID) AF: 0.00885 AC: 2 AN: 226

European-Non Finnish (NFE) AF: 0.00193 AC: 113 AN: 58586

Other (OTH) AF: 0.00120 AC: 2 AN: 1662

Alfa AF: 0.00 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;