chrX-54751014-C-A

Variant names:

• chrX-54751014-C-A
• rs142183856
• NM_198510.3:c.3719G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_198510.3(ITIH6):​c.3719G>T​(p.Arg1240Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000669 in 1,046,701 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1240G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000067 (0 hom. 2 hem.)
• Consequence: ITIH6 NM_198510.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33113676).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

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.3719G>T	p.Arg1240Leu	missense	Exon 12 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.3719G>T	p.Arg1240Leu	missense	Exon 12 of 13	ENSP00000218436.6	Q6UXX5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000277 AC: 3 AN: 108305 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000165

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: 0.00000669 AC: 7 AN: 1046701 Hom.: 0 Cov.: 31 AF XY: 0.00000597 AC XY: 2 AN XY: 334849

African (AFR) AF: 0.00 AC: 0 AN: 25351

American (AMR) AF: 0.000221 AC: 6 AN: 27139

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17429

East Asian (EAS) AF: 0.00 AC: 0 AN: 28228

South Asian (SAS) AF: 0.00 AC: 0 AN: 47699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37601

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3995

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 815249

Other (OTH) AF: 0.00 AC: 0 AN: 44010

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.045
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.24
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.17
Sift	Benign	0.031	D
Sift4G	Benign	0.27	T
Polyphen		0.17	B
Vest4		0.26
MutPred		0.80		Gain of helix (P = 0.062)
MVP		0.16
MPC		0.011
ClinPred		0.091	T
GERP RS		-4.4
Varity_R		0.12
gMVP		0.41
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs142183856; hg19: chrX-54777447;