10-122572320-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001377530.1(DMBT1):c.194C>T(p.Pro65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,176 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: DMBT1 NM_001377530.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.344

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00543952).
• BP6: Variant 10-122572320-C-T is Benign according to our data. Variant chr10-122572320-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3038002.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMBT1	NM_001377530.1	c.194C>T	p.Pro65Leu	missense_variant	5/56	ENST00000338354.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMBT1	ENST00000338354.10	c.194C>T	p.Pro65Leu	missense_variant	5/56	1	NM_001377530.1	P4

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 152150 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00143 AC: 356 AN: 249256 Hom.: 0 AF XY: 0.00133 AC XY: 180 AN XY: 135216

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00206 AC: 3010 AN: 1460908 Hom.: 5 Cov.: 31 AF XY: 0.00203 AC XY: 1473 AN XY: 726746

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00113

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00194 AC: 296 AN: 152268 Hom.: 1 Cov.: 33 AF XY: 0.00201 AC XY: 150 AN XY: 74472

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00234 Hom.: 3

Bravo AF: 0.00202

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000525 AC: 2

ESP6500EA AF: 0.00303 AC: 25

ExAC AF: 0.00135 AC: 163

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00249

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DMBT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2022

This variant is classified as likely 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	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	6.4
Dann	Benign	0.89
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00012	N
LIST_S2	Benign	0.48	T;.;.;T;.;T;T
M_CAP	Benign	0.00087	T
MetaRNN	Benign	0.0054	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.29	N;N;N;N;N;N;.
REVEL	Benign	0.011
Sift	Benign	0.17	T;T;D;T;T;D;.
Sift4G	Benign	0.62	T;T;T;T;T;T;T
Polyphen		0.19	B;B;B;B;P;B;P
Vest4		0.062
MVP		0.21
MPC		0.053
ClinPred		0.0034	T
GERP RS		-2.9
Varity_R		0.021
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs185045706; hg19: chr10-124331836; COSMIC: COSV57539888;