19-41355006-GGG-CGA

Variant names:

• chr19-41355006-GGG-CGA
• NM_030578.4:c.220_222delCCCinsTCG
• B9D2 p.Pro74Ser

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1_Very_Strong PM1 PP3

The NM_030578.4(B9D2):​c.220_222delCCCinsTCG​(p.Pro74Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P74P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: B9D2 NM_030578.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.77
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_030578.4 (B9D2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a domain C2 B9-type (size 116) in uniprot entity B9D2_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_030578.4
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D2	NM_030578.4	MANE Select	c.220_222delCCCinsTCG	p.Pro74Ser	missense	N/A	NP_085055.2	Q9BPU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D2	ENST00000243578.8	TSL:1 MANE Select	c.220_222delCCCinsTCG	p.Pro74Ser	missense	N/A	ENSP00000243578.2	Q9BPU9
	TMEM91	ENST00000539627.5	TSL:1	c.-30+3804_-30+3806delGGGinsCGA		intron	N/A	ENSP00000441900.1	F5GWC9
	B9D2	ENST00000675972.1		c.220_222delCCCinsTCG	p.Pro74Ser	missense	N/A	ENSP00000501911.1	Q9BPU9

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-41860911;