10-73193566-C-T

Position:

• chr10-73193566-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173348.2(FAM149B1):​c.515C>T​(p.Thr172Ile) 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 1,398,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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: -0.137

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]

DNAJC9 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05197099).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM149B1	NM_173348.2	c.515C>T	p.Thr172Ile	missense_variant	5/14	ENST00000242505.11	NP_775483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM149B1	ENST00000242505.11	c.515C>T	p.Thr172Ile	missense_variant	5/14	5	NM_173348.2	ENSP00000242505.6
FAM149B1	ENST00000372955.7	c.335C>T	p.Thr112Ile	missense_variant	3/10	1		ENSP00000362046.3
DNAJC9	ENST00000469143.1	n.148-9990G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398582 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 689846

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: 0.0000203

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Sep 12, 2023

The c.515C>T (p.T172I) alteration is located in exon 5 (coding exon 5) of the FAM149B1 gene. This alteration results from a C to T substitution at nucleotide position 515, causing the threonine (T) at amino acid position 172 to be replaced by an isoleucine (I). 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	0.084
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.020
Sift	Benign	0.24	T
Sift4G	Benign	0.090	T
Polyphen		0.0020	B
Vest4		0.081
MutPred		0.19		Loss of glycosylation at T172 (P = 0.0211);
MVP		0.030
ClinPred		0.038	T
GERP RS		-2.2
Varity_R		0.039
gMVP		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

Publications

LitVar

Other links and lift over

dbSNP: rs370830764; hg19: chr10-74953324;