10-73193550-G-T

Variant names:

• chr10-73193550-G-T
• rs61740304
• NM_173348.2:c.499G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_173348.2(FAM149B1):​c.499G>T​(p.Ala167Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 1,550,406 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A167T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: FAM149B1 NM_173348.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 1 publications found

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:19123): (DnaJ heat shock protein family (Hsp40) member C9) Enables chaperone binding activity; heat shock protein binding activity; and histone binding activity. Involved in nucleosome assembly and positive regulation of ATPase activity. Located in several cellular components, including cytosol; extracellular space; and nucleoplasm. Part of chaperone complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005445212).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00253 (385/152098) while in subpopulation AFR AF = 0.00882 (366/41476). AF 95% confidence interval is 0.00808. There are 1 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM149B1	NM_173348.2	c.499G>T	p.Ala167Ser	missense_variant	Exon 5 of 14	ENST00000242505.11	NP_775483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM149B1	ENST00000242505.11	c.499G>T	p.Ala167Ser	missense_variant	Exon 5 of 14	5	NM_173348.2	ENSP00000242505.6
FAM149B1	ENST00000372955.7	c.319G>T	p.Ala107Ser	missense_variant	Exon 3 of 10	1		ENSP00000362046.3
DNAJC9	ENST00000469143.1	n.148-9974C>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 383 AN: 151980 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00880

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000512 AC: 80 AN: 156308 AF XY: 0.000386

Gnomad AFR exome AF: 0.00859

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000200 AC: 279 AN: 1398308 Hom.: 0 Cov.: 30 AF XY: 0.000178 AC XY: 123 AN XY: 689744

African (AFR) AF: 0.00738 AC: 233 AN: 31572

American (AMR) AF: 0.000392 AC: 14 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35646

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49198

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5616

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078332

Other (OTH) AF: 0.000449 AC: 26 AN: 57938

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152098 Hom.: 1 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74352

African (AFR) AF: 0.00882 AC: 366 AN: 41476

American (AMR) AF: 0.000982 AC: 15 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000769 Hom.: 0

Bravo AF: 0.00241

ESP6500AA AF: 0.00795 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000696 AC: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.058
Sift	Benign	0.51	T
Sift4G	Benign	0.20	T
Polyphen		0.39	B
Vest4		0.13
MVP		0.030
ClinPred		0.020	T
GERP RS		2.9
Varity_R		0.036
gMVP		0.22
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61740304; hg19: chr10-74953308;