chr10-73177872-C-G

Position:

• chr10-73177872-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173348.2(FAM149B1):​c.179C>G​(p.Ser60Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM149B1 NM_173348.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26

Genes affected

FAM149B1 (HGNC:29162): (family with sequence similarity 149 member B1) Involved in cilium assembly and protein localization to cilium. Predicted to be located in cilium. Implicated in Joubert syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09529674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM149B1	NM_173348.2	c.179C>G	p.Ser60Cys	missense_variant	3/14	ENST00000242505.11	NP_775483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM149B1	ENST00000242505.11	c.179C>G	p.Ser60Cys	missense_variant	3/14	5	NM_173348.2	ENSP00000242505.6
FAM149B1	ENST00000372955	c.-2C>G		5_prime_UTR_variant	1/10	1		ENSP00000362046.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399478 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690238

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 10, 2023

The c.179C>G (p.S60C) alteration is located in exon 3 (coding exon 3) of the FAM149B1 gene. This alteration results from a C to G substitution at nucleotide position 179, causing the serine (S) at amino acid position 60 to be replaced by a cysteine (C). 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	Benign	0.082
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0062	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.055
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.048	D
Polyphen		0.95	P
Vest4		0.12
MutPred		0.13		Loss of phosphorylation at S60 (P = 0.0059);
MVP		0.055
ClinPred		0.48	T
GERP RS		4.4
Varity_R		0.12
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1749244375; hg19: chr10-74937630;