chr9-35906480-G-T

Variant names:

• chr9-35906480-G-T
• rs758542269
• NM_001039792.2:c.193G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001039792.2(HRCT1):​c.193G>T​(p.Gly65Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,457,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G65D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: HRCT1 NM_001039792.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50
• Publications: 0 publications found

Genes affected

HRCT1 (HGNC:33872): (histidine rich carboxyl terminus 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.19486362).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039792.2. 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
	HRCT1	NM_001039792.2	MANE Select	c.193G>T	p.Gly65Cys	missense	Exon 1 of 1	NP_001034881.1	Q6UXD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRCT1	ENST00000354323.3	TSL:6 MANE Select	c.193G>T	p.Gly65Cys	missense	Exon 1 of 1	ENSP00000346283.2	Q6UXD1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000363 AC: 9 AN: 247860 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000491

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457102 Hom.: 0 Cov.: 60 AF XY: 0.00000552 AC XY: 4 AN XY: 724842

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.000203 AC: 8 AN: 39338

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109818

Other (OTH) AF: 0.00 AC: 0 AN: 60122

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.11
Sift	Uncertain	0.028	D
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.18		Loss of disorder (P = 0.0888)
MVP		0.20
MPC		0.17
ClinPred		0.57	D
GERP RS		2.9
PromoterAI		-0.015	Neutral
Varity_R		0.29
gMVP		0.26
Mutation Taster		=90/10	polymorphism

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: rs758542269; hg19: chr9-35906477; COSMIC: COSV105915198; COSMIC: COSV105915198;