1-32361527-C-T

Position:

• chr1-32361527-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001167676.2(FAM229A):​c.290G>A​(p.Arg97His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000216 in 1,203,474 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: FAM229A NM_001167676.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

FAM229A (HGNC:44652): (family with sequence similarity 229 member A)

FAM229A (HGNC:):

TSSK3 (HGNC:15473): (testis specific serine kinase 3) This gene encodes a kinase expressed exclusively in the testis that is thought to play a role in either germ cell differentiation or mature sperm function. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM229A	NM_001167676.2	c.290G>A	p.Arg97His	missense_variant	3/3	ENST00000432622.2	NP_001161148.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM229A	ENST00000432622.2	c.290G>A	p.Arg97His	missense_variant	3/3	2	NM_001167676.2	ENSP00000455971.1
FAM229A	ENST00000416512.1	n.2503G>A		non_coding_transcript_exon_variant	2/2	1
FAM229A	ENST00000428500.1	c.133G>A	p.Val45Ile	missense_variant	2/2	2		ENSP00000454338.1
TSSK3	ENST00000574315.1	c.-80-2068C>T		intron_variant		3		ENSP00000459187.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000216 AC: 26 AN: 1203474 Hom.: 0 Cov.: 31 AF XY: 0.0000274 AC XY: 16 AN XY: 583056

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: 0.0000244

Gnomad4 OTH exome AF: 0.0000407

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.290G>A (p.R97H) alteration is located in exon 3 (coding exon 3) of the FAM229A gene. This alteration results from a G to A substitution at nucleotide position 290, causing the arginine (R) at amino acid position 97 to be replaced by a histidine (H). 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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.44	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.41
MVP		0.47
GERP RS		4.2
Varity_R		0.48
gMVP		0.22

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: rs952653339; hg19: chr1-32827128;