20-38926539-C-A

Variant names:

• chr20-38926539-C-A
• rs1187172593
• NM_030919.3:c.97C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030919.3(FAM83D):​c.97C>A​(p.Arg33Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM83D NM_030919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

Genes affected

FAM83D (HGNC:16122): (family with sequence similarity 83 member D) Enables kinesin binding activity; microtubule binding activity; and protein kinase binding activity. Involved in several processes, including positive regulation of cell cycle G1/S phase transition; protein localization to mitotic spindle; and regulation of intracellular signal transduction. Located in cytosol; intercellular bridge; and mitotic spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM83D	NM_030919.3	c.97C>A	p.Arg33Ser	missense_variant	Exon 1 of 4	ENST00000619850.2	NP_112181.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM83D	ENST00000619850.2	c.97C>A	p.Arg33Ser	missense_variant	Exon 1 of 4	1	NM_030919.3	ENSP00000481465.1
FAM83D	ENST00000619304.4	c.187C>A	p.Arg63Ser	missense_variant	Exon 1 of 4	1		ENSP00000481110.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433850 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 712986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.97C>A (p.L33M) alteration is located in exon 1 (coding exon 1) of the FAM83D gene. This alteration results from a C to A substitution at nucleotide position 97, causing the leucine (L) at amino acid position 33 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.8	.;H
PrimateAI	Pathogenic	0.89	D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.94
MutPred		0.86		.;Gain of phosphorylation at R33 (P = 0.0219);
MVP		0.50
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.46
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs1187172593; hg19: chr20-37555182;