NM_015681.6:c.*58G>A

Variant names:

• chr17-19343261-C-T
• rs534428777
• NM_015681.6:c.*58G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_015681.6(B9D1):​c.*58G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000904 in 1,611,532 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (2 hom.)
• Consequence: B9D1 NM_015681.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.40
• Publications: 0 publications found

Genes affected

B9D1 (HGNC:24123): (B9 domain containing 1) This gene encodes a B9 domain-containing protein, one of several that are involved in ciliogenesis. Alterations in expression of this gene have been found in a family with Meckel syndrome. Meckel syndrome has been associated with at least six different genes. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Mar 2016]

B9D1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 27

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Meckel syndrome, type 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000591 (90/152178) while in subpopulation NFE AF = 0.00101 (69/68026). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015681.6. 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
	B9D1	NM_015681.6	MANE Select	c.*58G>A		3_prime_UTR	Exon 7 of 7	NP_056496.1	Q9UPM9-1
	B9D1	NM_001321214.2		c.*198G>A		3_prime_UTR	Exon 7 of 7	NP_001308143.1	A8MYG7
	B9D1	NM_001321215.3		c.*449G>A		3_prime_UTR	Exon 6 of 6	NP_001308144.1	A0A2R8Y646

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B9D1	ENST00000261499.11	TSL:1 MANE Select	c.*58G>A		3_prime_UTR	Exon 7 of 7	ENSP00000261499.4	Q9UPM9-1
	B9D1	ENST00000663089.1		c.*449G>A		3_prime_UTR	Exon 7 of 7	ENSP00000499469.1	A0A590UJK9
	B9D1	ENST00000647252.1		c.*449G>A		3_prime_UTR	Exon 6 of 6	ENSP00000495045.1	A0A2R8Y646

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000937 AC: 1367 AN: 1459354 Hom.: 2 Cov.: 29 AF XY: 0.000894 AC XY: 649 AN XY: 725894

African (AFR) AF: 0.0000299 AC: 1 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.000349 AC: 30 AN: 86076

European-Finnish (FIN) AF: 0.00270 AC: 142 AN: 52588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5086

European-Non Finnish (NFE) AF: 0.00103 AC: 1149 AN: 1111422

Other (OTH) AF: 0.000730 AC: 44 AN: 60274

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.000552 AC XY: 41 AN XY: 74336

African (AFR) AF: 0.000121 AC: 5 AN: 41442

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000397

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Meckel syndrome, type 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.10
DANN	Benign	0.38
PhyloP100		-3.4
Mutation Taster		=100/0	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: rs534428777; hg19: chr17-19246574;