Genetic Variant NM_001005498.4:c.*342T>C (chr17-76471291-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001005498.4(RHBDF2):c.*342T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000075 in 266,692 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000087 ( 0 hom. )

Consequence

RHBDF2
NM_001005498.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.21

Publications

0 publications found

Variant links:

Genes affected

RHBDF2 (HGNC:20788): (rhomboid 5 homolog 2) Predicted to enable protein transporter activity. Predicted to be involved in negative regulation of protein secretion and regulation of epidermal growth factor receptor signaling pathway. Located in plasma membrane. Implicated in palmoplantar keratoderma-esophageal carcinoma syndrome. [provided by Alliance of Genome Resources, Apr 2022]

RHBDF2 Gene-Disease associations (from GenCC):

palmoplantar keratoderma-esophageal carcinoma syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

RHBDF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RHBDF2	NM_001005498.4	MANE Select	c.*342T>C	3_prime_UTR	Exon 19 of 19	NP_001005498.2	Q6PJF5-2
RHBDF2	NM_024599.5		c.*342T>C	3_prime_UTR	Exon 19 of 19	NP_078875.4	Q6PJF5-1
RHBDF2	NM_001376228.1		c.*342T>C	3_prime_UTR	Exon 19 of 19	NP_001363157.1	Q6PJF5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RHBDF2	ENST00000675367.1	MANE Select	c.*342T>C	3_prime_UTR	Exon 19 of 19	ENSP00000501790.1	Q6PJF5-2
RHBDF2	ENST00000313080.8	TSL:1	c.*342T>C	3_prime_UTR	Exon 19 of 19	ENSP00000322775.3	Q6PJF5-1
RHBDF2	ENST00000590168.5	TSL:1	n.2265T>C	non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151404

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000867

AC:

AN:

115288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

59840

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

4236

American (AMR)

AF:

0.00

AC:

AN:

4992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3608

East Asian (EAS)

AF:

0.00

AC:

AN:

7546

South Asian (SAS)

AF:

0.00

AC:

AN:

10826

European-Finnish (FIN)

AF:

0.000213

AC:

AN:

4686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

522

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

72334

Other (OTH)

AF:

0.00

AC:

AN:

6538

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151404

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73970

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40694

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Palmoplantar keratoderma-esophageal carcinoma syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.76

(source)

DANN

Benign

0.59

PhyloP100

-1.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over