rs2277244

chr10-122599067-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001377530.1(DMBT1):c.3250C>T(p.His1084Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0339 in 1,613,808 control chromosomes in the GnomAD database, including 1,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1172 hom.)
• Consequence: DMBT1 NM_001377530.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.34

Genes affected

DMBT1 (HGNC:2926): (deleted in malignant brain tumors 1) Loss of sequences from human chromosome 10q has been associated with the progression of human cancers. This gene was originally isolated based on its deletion in a medulloblastoma cell line. This gene is expressed with transcripts of 6.0, 7.5, and 8.0 kb in fetal lung and with one transcript of 8.0 kb in adult lung, although the 7.5 kb transcript has not been characterized. The encoded protein precursor is a glycoprotein containing multiple scavenger receptor cysteine-rich (SRCR) domains separated by SRCR-interspersed domains (SID). Transcript variant 2 (8.0 kb) has been shown to bind surfactant protein D independently of carbohydrate recognition. This indicates that DMBT1 may not be a classical tumor suppressor gene, but rather play a role in the interaction of tumor cells and the immune system. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030488968).
• BP6: Variant 10-122599067-C-T is Benign according to our data. Variant chr10-122599067-C-T is described in ClinVar as [Benign]. Clinvar id is 3037168.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMBT1	NM_001377530.1	c.3250C>T	p.His1084Tyr	missense_variant	26/56	ENST00000338354.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMBT1	ENST00000338354.10	c.3250C>T	p.His1084Tyr	missense_variant	26/56	1	NM_001377530.1	P4

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4124 AN: 152160 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0308

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0401 AC: 9987 AN: 249032 Hom.: 286 AF XY: 0.0426 AC XY: 5756 AN XY: 135088

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.0434

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.0793

Gnomad SAS exome AF: 0.0750

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0346 AC: 50546 AN: 1461530 Hom.: 1172 Cov.: 34 AF XY: 0.0358 AC XY: 26009 AN XY: 727054

Gnomad4 AFR exome AF: 0.00612

Gnomad4 AMR exome AF: 0.0422

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.0910

Gnomad4 SAS exome AF: 0.0759

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0302

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0272 AC: 4135 AN: 152278 Hom.: 85 Cov.: 32 AF XY: 0.0284 AC XY: 2113 AN XY: 74454

Gnomad4 AFR AF: 0.00758

Gnomad4 AMR AF: 0.0307

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.0689

Gnomad4 SAS AF: 0.0819

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.0308

Gnomad4 OTH AF: 0.0299

Alfa AF: 0.0282 Hom.: 23

Bravo AF: 0.0258

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0296 AC: 114

ESP6500AA AF: 0.00911 AC: 35

ESP6500EA AF: 0.0290 AC: 240

ExAC AF: 0.0410 AC: 4955

Asia WGS AF: 0.0790 AC: 277 AN: 3478

EpiCase AF: 0.0335

EpiControl AF: 0.0299

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DMBT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.;.;D;.;D;D
MetaRNN	Benign	0.0030	T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.6	H;.;.;.;H;.;H
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D;D;D;D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.30
MPC		0.058
ClinPred		0.091	T
GERP RS		3.6
Varity_R		0.69
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2277244; hg19: chr10-124358583; COSMIC: COSV57545155;