rs113994185

Variant names:

• chr15-72686244-T-C
• rs113994185
• NM_033028.5:c.17T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-72686244-T-C
• chr15-72686244-T-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_033028.5(BBS4):​c.17T>C​(p.Val6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,413,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V6G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.102
• Publications: 1 publications found

Genes affected

BBS4 (HGNC:969): (Bardet-Biedl syndrome 4) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein's shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein "BBSome" complex with seven other BBS proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

HIGD2B (HGNC:26984): (HIG1 hypoxia inducible domain family member 2B) Predicted to be involved in mitochondrial respirasome assembly. Predicted to be integral component of membrane. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055848926).
• BP6: Variant 15-72686244-T-C is Benign according to our data. Variant chr15-72686244-T-C is described in ClinVar as Benign. ClinVar VariationId is 21736.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033028.5. 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
	BBS4	NM_033028.5	MANE Select	c.17T>C	p.Val6Ala	missense	Exon 1 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.17T>C	p.Val6Ala	missense	Exon 1 of 15	NP_001307594.1
	BBS4	NR_045565.2		n.38T>C		non_coding_transcript_exon	Exon 1 of 17

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.17T>C	p.Val6Ala	missense	Exon 1 of 16	ENSP00000268057.4
	BBS4	ENST00000562084.5	TSL:1	n.17T>C		non_coding_transcript_exon	Exon 1 of 16	ENSP00000454718.1
	BBS4	ENST00000395205.7	TSL:1	c.-448T>C		5_prime_UTR	Exon 1 of 15	ENSP00000378631.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000568 AC: 1 AN: 176176 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413276 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698472

African (AFR) AF: 0.00 AC: 0 AN: 32290

American (AMR) AF: 0.00 AC: 0 AN: 37910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.00 AC: 0 AN: 37030

South Asian (SAS) AF: 0.00 AC: 0 AN: 80206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4714

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088010

Other (OTH) AF: 0.00 AC: 0 AN: 58470

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Bardet-Biedl syndrome Benign:1

Oct 13, 2009

GeneReviews

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	1.0
DANN	Benign	0.85
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.10
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.17
Sift	Benign	0.49	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.15		Loss of helix (P = 0.079)
MVP		0.54
MPC		0.012
ClinPred		0.081	T
GERP RS		-1.5
PromoterAI		-0.064	Neutral
Varity_R		0.048
gMVP		0.29
Mutation Taster		=94/6	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: rs113994185; hg19: chr15-72978585;