10-122570905-C-G

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.155C>G(p.Ser52Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,340 control chromosomes in the GnomAD database, including 1,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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 0.057 (776 hom., cov: 33)
  • Exomes 𝑓: 0.011 (733 hom.)
• Consequence: DMBT1 NM_001377530.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.139

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=0.0013635755).
• BP6: Variant 10-122570905-C-G is Benign according to our data. Variant chr10-122570905-C-G is described in ClinVar as [Benign]. Clinvar id is 3037372.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMBT1	NM_001377530.1	c.155C>G	p.Ser52Trp	missense_variant	4/56	ENST00000338354.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMBT1	ENST00000338354.10	c.155C>G	p.Ser52Trp	missense_variant	4/56	1	NM_001377530.1	P4

Frequencies

GnomAD3 genomes AF: 0.0572 AC: 8701 AN: 152116 Hom.: 771 Cov.: 33

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00584

Gnomad OTH AF: 0.0460

GnomAD3 exomes AF: 0.0172 AC: 4290 AN: 249214 Hom.: 314 AF XY: 0.0140 AC XY: 1893 AN XY: 135198

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.00567

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0106 AC: 15555 AN: 1461106 Hom.: 733 Cov.: 31 AF XY: 0.00983 AC XY: 7148 AN XY: 726904

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.00693

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00598

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0573 AC: 8717 AN: 152234 Hom.: 776 Cov.: 33 AF XY: 0.0559 AC XY: 4159 AN XY: 74438

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0237

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00582

Gnomad4 OTH AF: 0.0455

Alfa AF: 0.00917 Hom.: 26

Bravo AF: 0.0647

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.175 AC: 658

ESP6500EA AF: 0.00619 AC: 51

ExAC AF: 0.0198 AC: 2394

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00699

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

Jun 05, 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	Benign	0.28
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.61	T;.;.;T;.;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.67	N;N;N;N;N;N;.
REVEL	Benign	0.089
Sift	Uncertain	0.015	D;D;D;D;D;D;.
Sift4G	Benign	0.071	T;T;D;T;T;D;T
Polyphen		0.57	P;P;P;P;D;P;D
Vest4		0.19
MPC		0.36
ClinPred		0.035	T
GERP RS		0.97
Varity_R		0.070
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75209396; hg19: chr10-124330421;