11-532746-C-T

Variant names:

• chr11-532746-C-T
• rs745497215
• NM_005343.4:c.460G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4 BP6 BS1

The NM_005343.4(HRAS):​c.460G>A​(p.Asp154Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,612,728 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D154Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.90
• Publications: 7 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 26 uncertain in NM_005343.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.4155776).
• BP6: Variant 11-532746-C-T is Benign according to our data. Variant chr11-532746-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 40445.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000116 (17/1460486) while in subpopulation AMR AF = 0.000201 (9/44722). AF 95% confidence interval is 0.000104. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.460G>A	p.Asp154Asn	missense	Exon 5 of 6	NP_005334.1
	HRAS	NM_176795.5	MANE Plus Clinical	c.*29G>A		3_prime_UTR	Exon 6 of 6	NP_789765.1
	HRAS	NM_001130442.3		c.460G>A	p.Asp154Asn	missense	Exon 5 of 5	NP_001123914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.460G>A	p.Asp154Asn	missense	Exon 5 of 6	ENSP00000309845.7
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.*29G>A		3_prime_UTR	Exon 6 of 6	ENSP00000388246.1
	HRAS	ENST00000493230.5	TSL:1	n.*29G>A		non_coding_transcript_exon	Exon 6 of 7	ENSP00000434023.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000282 AC: 7 AN: 247850 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460486 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726570

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111966

Other (OTH) AF: 0.0000663 AC: 4 AN: 60376

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74370

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000218322), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Costello syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.22
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.64	N
PhyloP100		3.9
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Benign	0.073	T
Polyphen		0.11	B
Vest4		0.55
MutPred		0.56		Gain of MoRF binding (P = 0.0331)
MVP		0.77
MPC		1.1
ClinPred		0.11	T
GERP RS		3.5
Varity_R		0.43
gMVP		0.52
Mutation Taster		=44/56	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: rs745497215; hg19: chr11-532746;