rs747988749

Variant names:

• chr19-41357961-C-G
• rs747988749
• NM_030578.4:c.150G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4 BS1_Supporting

The NM_030578.4(B9D2):​c.150G>C​(p.Gln50His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: B9D2 NM_030578.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.00500
• Publications: 1 publications found

Genes affected

B9D2 (HGNC:28636): (B9 domain containing 2) This gene encodes a B9 domain protein, which are exclusively found in ciliated organisms. The gene is upregulated during mucociliary differentiation, and the encoded protein localizes to basal bodies and cilia. Disrupting expression of this gene results in ciliogenesis defects. [provided by RefSeq, Oct 2009]

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255730 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a chain B9 domain-containing protein 2 (size 174) in uniprot entity B9D2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_030578.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.26497722).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000239 (35/1461862) while in subpopulation AMR AF = 0.000783 (35/44722). AF 95% confidence interval is 0.000578. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030578.4. 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
	B9D2	NM_030578.4	MANE Select	c.150G>C	p.Gln50His	missense	Exon 3 of 4	NP_085055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D2	ENST00000243578.8	TSL:1 MANE Select	c.150G>C	p.Gln50His	missense	Exon 3 of 4	ENSP00000243578.2
	TMEM91	ENST00000539627.5	TSL:1	c.-30+6759C>G		intron	N/A	ENSP00000441900.1
	B9D2	ENST00000675972.1		c.150G>C	p.Gln50His	missense	Exon 3 of 4	ENSP00000501911.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251388 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461862 Hom.: 0 Cov.: 34 AF XY: 0.0000220 AC XY: 16 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000123 AC: 15

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.0050
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.45
Sift	Benign	0.11	T
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.45		Loss of catalytic residue at Q50 (P = 0.0172)
MVP		0.57
MPC		0.32
ClinPred		0.49	T
GERP RS		-0.82
Varity_R		0.37
gMVP		0.43
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs747988749; hg19: chr19-41863866; COSMIC: COSV54683499; COSMIC: COSV54683499;