10-101611284-C-G

Variant names:

• chr10-101611284-C-G
• rs73349895
• NM_022039.4:c.*7G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022039.4(FBXW4):​c.*7G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00729 in 1,612,714 control chromosomes in the GnomAD database, including 634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (324 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (310 hom.)
• Consequence: FBXW4 NM_022039.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.548
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-101611284-C-G is Benign according to our data. Variant chr10-101611284-C-G is described in ClinVar as Benign. ClinVar VariationId is 298527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

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.*7G>C		3_prime_UTR	Exon 9 of 9	NP_071322.2	A0A5F9UQ55
	FBXW4	NM_001323541.2		c.*7G>C		3_prime_UTR	Exon 9 of 9	NP_001310470.1
	FBXW4	NR_136613.2		n.1681G>C		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.*7G>C		3_prime_UTR	Exon 9 of 9	ENSP00000359149.3	A0A5F9UQ55
	FBXW4	ENST00000945850.1		c.*7G>C		3_prime_UTR	Exon 10 of 10	ENSP00000615909.1
	FBXW4	ENST00000945851.1		c.*7G>C		3_prime_UTR	Exon 9 of 9	ENSP00000615910.1

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5446 AN: 152146 Hom.: 322 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.00995 AC: 2489 AN: 250144 AF XY: 0.00726

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00670

Gnomad ASJ exome AF: 0.00581

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.00431 AC: 6288 AN: 1460450 Hom.: 310 Cov.: 31 AF XY: 0.00387 AC XY: 2813 AN XY: 726478

African (AFR) AF: 0.131 AC: 4377 AN: 33454

American (AMR) AF: 0.00800 AC: 357 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00510 AC: 133 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000395 AC: 34 AN: 86028

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53326

Middle Eastern (MID) AF: 0.0134 AC: 73 AN: 5468

European-Non Finnish (NFE) AF: 0.000643 AC: 715 AN: 1111480

Other (OTH) AF: 0.00988 AC: 596 AN: 60304

GnomAD4 genome AF: 0.0359 AC: 5462 AN: 152264 Hom.: 324 Cov.: 33 AF XY: 0.0347 AC XY: 2582 AN XY: 74466

African (AFR) AF: 0.122 AC: 5065 AN: 41522

American (AMR) AF: 0.0163 AC: 250 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68020

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.00275 Hom.: 3

Bravo AF: 0.0408

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Split hand-foot malformation 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.7
DANN	Benign	0.62
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs73349895; hg19: chr10-103371041;