10-101770141-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAA

Variant names:

• chr10-101770141-T-TAAA
• rs11322844
• NM_033163.5:c.*185_*187dupTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_033163.5(FGF8):​c.*185_*187dupTTT 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 0.00025 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0030 (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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000248 (30/120760) while in subpopulation NFE AF = 0.000358 (21/58592). AF 95% confidence interval is 0.000239. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF8	NM_033163.5	c.*185_*187dupTTT		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.*185_*187dupTTT		3_prime_UTR_variant	Exon 6 of 6	1	NM_033163.5	ENSP00000321797.2

Frequencies

GnomAD3 genomes AF: 0.000248 AC: 30 AN: 120778 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000248

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000267

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000358

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00297 AC: 805 AN: 271022 Hom.: 0 Cov.: 0 AF XY: 0.00302 AC XY: 421 AN XY: 139178

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

African (AFR) AF: 0.00616 AC: 46 AN: 7462

American (AMR) AF: 0.00184 AC: 18 AN: 9766

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 10 AN: 9042

East Asian (EAS) AF: 0.000879 AC: 19 AN: 21606

South Asian (SAS) AF: 0.00186 AC: 28 AN: 15086

European-Finnish (FIN) AF: 0.00229 AC: 45 AN: 19644

Middle Eastern (MID) AF: 0.000806 AC: 1 AN: 1240

European-Non Finnish (NFE) AF: 0.00352 AC: 601 AN: 170636

Other (OTH) AF: 0.00224 AC: 37 AN: 16540

⚠️ 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: 0.000248 AC: 30 AN: 120760 Hom.: 0 Cov.: 0 AF XY: 0.000262 AC XY: 15 AN XY: 57200

African (AFR) AF: 0.000158 AC: 5 AN: 31612

American (AMR) AF: 0.000248 AC: 3 AN: 12100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3022

East Asian (EAS) AF: 0.00 AC: 0 AN: 4218

South Asian (SAS) AF: 0.000269 AC: 1 AN: 3712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4796

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

European-Non Finnish (NFE) AF: 0.000358 AC: 21 AN: 58592

Other (OTH) AF: 0.00 AC: 0 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;