rs138272051

Variant names:

• chr11-533799-T-G
• rs138272051
• NM_005343.4:c.257A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-533799-T-G
• chr11-533799-T-A
• chr11-533799-T-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP5

This summary comes from the ClinGen Evidence Repository: The c.257A>C variant in the HRAS gene is a missense variant predicted to cause substitution of asparagine by threonine at amino acid 86 (p.Asn86Thr). The filtering allele frequency in gnomAD v2.1.1 is 0.0006669 (22/24924 alleles) in the Latino/Admixed American population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.367, which is neither above nor below the thresholds predicting a damaging or benign impact on HRAS function. This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data GTR ID: 21766, 26957, ClinVar SCV000204177.4, SCV000207861.7). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA180888/MONDO:0021060/046

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 4.10
• Publications: 8 publications found

Genes affected

HRAS (HGNC:5173): (HRas proto-oncogene, GTPase) This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]

LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005343.4. 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
	HRAS	NM_005343.4	MANE Select	c.257A>C	p.Asn86Thr	missense	Exon 3 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.257A>C	p.Asn86Thr	missense	Exon 3 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.257A>C	p.Asn86Thr	missense	Exon 3 of 5	NP_001123914.1	X5D945

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.257A>C	p.Asn86Thr	missense	Exon 3 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.257A>C	p.Asn86Thr	missense	Exon 3 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.257A>C		non_coding_transcript_exon	Exon 3 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251296 AF XY: 0.000155

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461110 Hom.: 0 Cov.: 34 AF XY: 0.000110 AC XY: 80 AN XY: 726882

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52664

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1111996

Other (OTH) AF: 0.000248 AC: 15 AN: 60386

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74424

African (AFR) AF: 0.000746 AC: 31 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 67990

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000375 Hom.: 0

Bravo AF: 0.000378

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	Costello syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	HRAS-related disorder (1)
-	-	1	Noonan syndrome (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	0.076
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.090	T
Polyphen		0.36	B
Vest4		0.50
MVP		0.79
MPC		1.2
ClinPred		0.032	T
GERP RS		3.6
PromoterAI		-0.014	Neutral
Varity_R		0.75
gMVP		0.67
Mutation Taster		=39/61	disease causing

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: rs138272051; hg19: chr11-533799;