rs387906223

Variant names:

• chr3-49171662-C-T
• rs387906223
• NM_173546.3:c.-158C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The NM_173546.3(KLHDC8B):​c.-158C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 152,510 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 33)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: KLHDC8B NM_173546.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 0.456
• Publications: 4 publications found

Genes affected

KLHDC8B (HGNC:28557): (kelch domain containing 8B) This gene encodes a protein which forms a distinct beta-propeller protein structure of kelch domains allowing for protein-protein interactions. Mutations in this gene have been associated with Hodgkin lymphoma. [provided by RefSeq, Sep 2010]

KLHDC8B Gene-Disease associations (from GenCC):

• classic Hodgkin lymphoma

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-49171662-C-T is Benign according to our data. Variant chr3-49171662-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 718 AD,Unknown gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173546.3. 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
	KLHDC8B	NM_173546.3	MANE Select	c.-158C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_775817.1	Q8IXV7
	KLHDC8B	NM_173546.3	MANE Select	c.-158C>T		5_prime_UTR	Exon 1 of 6	NP_775817.1	Q8IXV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC8B	ENST00000332780.4	TSL:1 MANE Select	c.-158C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000327468.2	Q8IXV7
	KLHDC8B	ENST00000332780.4	TSL:1 MANE Select	c.-158C>T		5_prime_UTR	Exon 1 of 6	ENSP00000327468.2	Q8IXV7
	KLHDC8B	ENST00000948547.1		c.-158C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000618606.1

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 718 AN: 152248 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00807

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.0208 AC: 3 AN: 144 Hom.: 0 Cov.: 0 AF XY: 0.0273 AC XY: 3 AN XY: 110

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0242 AC: 3 AN: 124

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.00471 AC: 718 AN: 152366 Hom.: 2 Cov.: 33 AF XY: 0.00431 AC XY: 321 AN XY: 74504

African (AFR) AF: 0.00156 AC: 65 AN: 41598

American (AMR) AF: 0.00229 AC: 35 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00461 AC: 49 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00807 AC: 549 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00351 Hom.: 0

Bravo AF: 0.00446

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Classic Hodgkin lymphoma (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.9
DANN	Benign	0.69
PhyloP100		0.46
PromoterAI		-0.22	Neutral
Mutation Taster		=300/0	disease causing (ClinVar)

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: rs387906223; hg19: chr3-49209095;