rs678

Variant names:

• chr3-52786965-A-T
• rs678
• NM_002215.4:c.1754A>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52786965-A-T
• chr3-52786965-A-C
• chr3-52786965-A-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002215.4(ITIH1):​c.1754A>T​(p.Glu585Val) variant causes a missense change. The variant allele was found at a frequency of 0.35 in 1,612,586 control chromosomes in the GnomAD database, including 102,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8340 hom., cov: 33)
  • Exomes 𝑓: 0.35 (94567 hom.)
• Consequence: ITIH1 NM_002215.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.05
• Publications: 60 publications found

Genes affected

ITIH1 (HGNC:6166): (inter-alpha-trypsin inhibitor heavy chain 1) This gene encodes a member of the inter-alpha-trypsin inhibitor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the heavy chain of the inter-alpha-trypsin inhibitor complex, which is secreted by hepatocytes into the blood. The heavy chain also interacts with hyaluronan, and this interaction may play a role in ovulation and fertilization, and has been implicated in multiple inflammatory diseases. This gene is present in a gene cluster on chromosome 3. [provided by RefSeq, Nov 2015]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-52786965-A-T is Benign according to our data. Variant chr3-52786965-A-T is described in ClinVar as Benign. ClinVar VariationId is 487489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002215.4. 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
	ITIH1	NM_002215.4	MANE Select	c.1754A>T	p.Glu585Val	missense	Exon 14 of 22	NP_002206.2	P19827-1
	ITIH1	NM_001166434.3		c.1328A>T	p.Glu443Val	missense	Exon 12 of 20	NP_001159906.1	P19827-2
	ITIH1	NM_001166435.2		c.890A>T	p.Glu297Val	missense	Exon 10 of 18	NP_001159907.1	P19827-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH1	ENST00000273283.7	TSL:1 MANE Select	c.1754A>T	p.Glu585Val	missense	Exon 14 of 22	ENSP00000273283.2	P19827-1
	ITIH1	ENST00000943717.1		c.1754A>T	p.Glu585Val	missense	Exon 14 of 22	ENSP00000613776.1
	ITIH1	ENST00000943715.1		c.1754A>T	p.Glu585Val	missense	Exon 14 of 22	ENSP00000613774.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47383 AN: 151810 Hom.: 8339 Cov.: 33

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.337

GnomAD2 exomes AF: 0.358 AC: 89532 AN: 250182 AF XY: 0.349

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.357

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.354 AC: 517462 AN: 1460658 Hom.: 94567 Cov.: 47 AF XY: 0.350 AC XY: 254097 AN XY: 726544

African (AFR) AF: 0.144 AC: 4814 AN: 33452

American (AMR) AF: 0.510 AC: 22730 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 11602 AN: 26064

East Asian (EAS) AF: 0.426 AC: 16915 AN: 39682

South Asian (SAS) AF: 0.201 AC: 17319 AN: 86172

European-Finnish (FIN) AF: 0.366 AC: 19542 AN: 53384

Middle Eastern (MID) AF: 0.390 AC: 2243 AN: 5752

European-Non Finnish (NFE) AF: 0.362 AC: 401957 AN: 1111214

Other (OTH) AF: 0.337 AC: 20340 AN: 60332

GnomAD4 genome AF: 0.312 AC: 47408 AN: 151928 Hom.: 8340 Cov.: 33 AF XY: 0.314 AC XY: 23280 AN XY: 74254

African (AFR) AF: 0.153 AC: 6331 AN: 41504

American (AMR) AF: 0.443 AC: 6767 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1494 AN: 3462

East Asian (EAS) AF: 0.369 AC: 1903 AN: 5160

South Asian (SAS) AF: 0.201 AC: 968 AN: 4814

European-Finnish (FIN) AF: 0.354 AC: 3739 AN: 10550

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 24980 AN: 67860

Other (OTH) AF: 0.342 AC: 722 AN: 2110

Alfa AF: 0.358 Hom.: 3527

Bravo AF: 0.315

TwinsUK AF: 0.350 AC: 1298

ALSPAC AF: 0.355 AC: 1368

ESP6500AA AF: 0.147 AC: 646

ESP6500EA AF: 0.379 AC: 3261

ExAC AF: 0.349 AC: 42390

Asia WGS AF: 0.300 AC: 1040 AN: 3478

EpiCase AF: 0.381

EpiControl AF: 0.372

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.1
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.23
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.21
MPC		0.71
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.61
gMVP		0.73
Mutation Taster		=27/73	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs678; hg19: chr3-52820981; COSMIC: COSV56251847; COSMIC: COSV56251847;