chr10-73240981-G-A

Variant names:

• chr10-73240981-G-A
• rs12573841
• NM_173348.2:c.1711G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173348.2(FAM149B1):​c.1711G>A​(p.Gly571Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,499,480 control chromosomes in the GnomAD database, including 6,597 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.082 (640 hom., cov: 31)
  • Exomes 𝑓: 0.075 (5957 hom.)
• Consequence: FAM149B1 NM_173348.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 24 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035297573).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173348.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM149B1	NM_173348.2	MANE Select	c.1711G>A	p.Gly571Arg	missense	Exon 14 of 14	NP_775483.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM149B1	ENST00000242505.11	TSL:5 MANE Select	c.1711G>A	p.Gly571Arg	missense	Exon 14 of 14	ENSP00000242505.6
	FAM149B1	ENST00000445951.5	TSL:5	c.970G>A	p.Gly324Arg	missense	Exon 8 of 8	ENSP00000402293.1
	FAM149B1	ENST00000468462.1	TSL:2	n.1320G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0824 AC: 10921 AN: 132606 Hom.: 640 Cov.: 31

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0653

Gnomad ASJ AF: 0.0965

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.0429

Gnomad MID AF: 0.0408

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.0740

GnomAD2 exomes AF: 0.103 AC: 16091 AN: 156642 AF XY: 0.111

Gnomad AFR exome AF: 0.0725

Gnomad AMR exome AF: 0.0646

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.0596

Gnomad OTH exome AF: 0.0827

GnomAD4 exome AF: 0.0746 AC: 102026 AN: 1366826 Hom.: 5957 Cov.: 27 AF XY: 0.0789 AC XY: 53266 AN XY: 675474

African (AFR) AF: 0.0847 AC: 1708 AN: 20164

American (AMR) AF: 0.0647 AC: 2243 AN: 34664

Ashkenazi Jewish (ASJ) AF: 0.0979 AC: 2384 AN: 24352

East Asian (EAS) AF: 0.323 AC: 10120 AN: 31290

South Asian (SAS) AF: 0.212 AC: 16586 AN: 78066

European-Finnish (FIN) AF: 0.0466 AC: 2227 AN: 47772

Middle Eastern (MID) AF: 0.0514 AC: 271 AN: 5270

European-Non Finnish (NFE) AF: 0.0577 AC: 61776 AN: 1069850

Other (OTH) AF: 0.0850 AC: 4711 AN: 55398

GnomAD4 genome AF: 0.0825 AC: 10941 AN: 132654 Hom.: 640 Cov.: 31 AF XY: 0.0854 AC XY: 5549 AN XY: 64988

African (AFR) AF: 0.0959 AC: 2396 AN: 24992

American (AMR) AF: 0.0653 AC: 938 AN: 14362

Ashkenazi Jewish (ASJ) AF: 0.0965 AC: 321 AN: 3328

East Asian (EAS) AF: 0.342 AC: 1566 AN: 4574

South Asian (SAS) AF: 0.221 AC: 1039 AN: 4712

European-Finnish (FIN) AF: 0.0429 AC: 434 AN: 10128

Middle Eastern (MID) AF: 0.0435 AC: 12 AN: 276

European-Non Finnish (NFE) AF: 0.0593 AC: 4006 AN: 67510

Other (OTH) AF: 0.0774 AC: 144 AN: 1860

Alfa AF: 0.0784 Hom.: 1227

Bravo AF: 0.157

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0571 AC: 220

ExAC AF: 0.118 AC: 2876

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.00097	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.5	N
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	3.2	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.040
MutPred		0.067		Gain of catalytic residue at G571 (P = 0.0331)
ClinPred		0.0090	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.083
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12573841; hg19: chr10-75000739; COSMIC: COSV54351349; COSMIC: COSV54351349;