chr9-35906477-C-T

Variant names:

• chr9-35906477-C-T
• rs765274731
• NM_001039792.2:c.190C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001039792.2(HRCT1):​c.190C>T​(p.Arg64Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,612,526 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R64Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (1 hom.)
• Consequence: HRCT1 NM_001039792.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.608
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41309714).

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.190C>T	p.Arg64Trp	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.190C>T	p.Arg64Trp	missense	Exon 1 of 1	ENSP00000346283.2	Q6UXD1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000605 AC: 15 AN: 247938 AF XY: 0.0000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1460524 Hom.: 1 Cov.: 59 AF XY: 0.0000358 AC XY: 26 AN XY: 726576

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000693 AC: 31 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52238

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111908

Other (OTH) AF: 0.0000497 AC: 3 AN: 60374

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74246

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.000524 AC: 8 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0057	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.61
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Benign	0.090	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.51
MutPred		0.28		Loss of disorder (P = 0.0011)
MVP		0.25
MPC		0.13
ClinPred		0.23	T
GERP RS		4.0
PromoterAI		-0.070	Neutral
Varity_R		0.063
gMVP		0.23
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs765274731; hg19: chr9-35906474;