10-101611087-C-T

Variant names:

• chr10-101611087-C-T
• rs185181909
• NM_022039.4:c.*204G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_022039.4(FBXW4):​c.*204G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 588,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: FBXW4 NM_022039.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.306
• Publications: 0 publications found

Genes affected

FBXW4 (HGNC:10847): (F-box and WD repeat domain containing 4) This gene is a member of the F-box/WD-40 gene family, which recruit specific target proteins through their WD-40 protein-protein binding domains for ubiquitin mediated degradation. In mouse, a highly similar protein is thought to be responsible for maintaining the apical ectodermal ridge of developing limb buds; disruption of the mouse gene results in the absence of central digits, underdeveloped or absent metacarpal/metatarsal bones and syndactyly. This phenotype is remarkably similar to split hand-split foot malformation in humans, a clinically heterogeneous condition with a variety of modes of transmission. An autosomal recessive form has been mapped to the chromosomal region where this gene is located, and complex rearrangements involving duplications of this gene and others have been associated with the condition. A pseudogene of this locus has been mapped to one of the introns of the BCR gene on chromosome 22. [provided by RefSeq, Jul 2008]

FBXW4 Gene-Disease associations (from GenCC):

• split hand-foot malformation 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 10-101611087-C-T is Benign according to our data. Variant chr10-101611087-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 879144.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 68 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022039.4. 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
	FBXW4	NM_022039.4	MANE Select	c.*204G>A		3_prime_UTR	Exon 9 of 9	NP_071322.2	A0A5F9UQ55
	FBXW4	NM_001323541.2		c.*204G>A		3_prime_UTR	Exon 9 of 9	NP_001310470.1
	FBXW4	NR_136613.2		n.1878G>A		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW4	ENST00000331272.9	TSL:1 MANE Select	c.*204G>A		3_prime_UTR	Exon 9 of 9	ENSP00000359149.3	A0A5F9UQ55
	FBXW4	ENST00000945850.1		c.*204G>A		3_prime_UTR	Exon 10 of 10	ENSP00000615909.1
	FBXW4	ENST00000945851.1		c.*204G>A		3_prime_UTR	Exon 9 of 9	ENSP00000615910.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000515 AC: 225 AN: 436540 Hom.: 0 Cov.: 6 AF XY: 0.000449 AC XY: 102 AN XY: 227326

African (AFR) AF: 0.00 AC: 0 AN: 11806

American (AMR) AF: 0.00153 AC: 23 AN: 15022

Ashkenazi Jewish (ASJ) AF: 0.000334 AC: 4 AN: 11982

East Asian (EAS) AF: 0.00 AC: 0 AN: 25410

South Asian (SAS) AF: 0.00 AC: 0 AN: 40762

European-Finnish (FIN) AF: 0.0000401 AC: 1 AN: 24964

Middle Eastern (MID) AF: 0.000566 AC: 1 AN: 1766

European-Non Finnish (NFE) AF: 0.000566 AC: 159 AN: 280974

Other (OTH) AF: 0.00155 AC: 37 AN: 23854

GnomAD4 genome AF: 0.000446 AC: 68 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74508

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.00203 AC: 31 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68040

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000650

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Split hand-foot malformation 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.31

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: rs185181909; hg19: chr10-103370844;