NM_198510.3:c.3742C>A

Variant names:

• chrX-54750095-G-T
• rs762777909
• NM_198510.3:c.3742C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198510.3(ITIH6):​c.3742C>A​(p.His1248Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,822 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 (★). Synonymous variant affecting the same amino acid position (i.e. H1248H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: ITIH6 NM_198510.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

Genes affected

ITIH6 (HGNC:28907): (inter-alpha-trypsin inhibitor heavy chain family member 6) The protein encoded by this gene belongs to the interalpha trypsin inhibitor heavy chain (ITIH) family. Interalpha trypsin inhibitor (ITI) is composed of two heavy chains (containing VWA domain) and one light chain. The light chain confers the protease-inhibitor function, while the heavy chains are involved in mediating protein-protein interactions with the components of the extracellular matrix. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08300984).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198510.3. 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
	ITIH6	NM_198510.3	MANE Select	c.3742C>A	p.His1248Asn	missense	Exon 13 of 13	NP_940912.1	Q6UXX5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH6	ENST00000218436.7	TSL:1 MANE Select	c.3742C>A	p.His1248Asn	missense	Exon 13 of 13	ENSP00000218436.6	Q6UXX5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000569 AC: 1 AN: 175630 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000374

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090822 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 356716

African (AFR) AF: 0.00 AC: 0 AN: 26287

American (AMR) AF: 0.0000286 AC: 1 AN: 34924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19089

East Asian (EAS) AF: 0.00 AC: 0 AN: 30093

South Asian (SAS) AF: 0.00 AC: 0 AN: 53096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40365

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837509

Other (OTH) AF: 0.00 AC: 0 AN: 45749

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.6
DANN	Benign	0.50
DEOGEN2	Benign	0.0028	T
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.063
Sift	Benign	0.36	T
Sift4G	Benign	0.41	T
Polyphen		0.043	B
Vest4		0.30
MutPred		0.31		Gain of sheet (P = 0.1945)
MVP		0.45
MPC		0.025
ClinPred		0.093	T
GERP RS		1.7
Varity_R		0.10
gMVP		0.34
Mutation Taster		=90/10	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: rs762777909; hg19: chrX-54776528;