10-122579701-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.803C>T(p.Ala268Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,872 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (10 hom.)
• Consequence: DMBT1 NM_001377530.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.04

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=0.007470429).
• BP6: Variant 10-122579701-C-T is Benign according to our data. Variant chr10-122579701-C-T is described in ClinVar as [Benign]. Clinvar id is 3034279.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.803C>T	p.Ala268Val	missense_variant	10/56	ENST00000338354.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMBT1	ENST00000338354.10	c.803C>T	p.Ala268Val	missense_variant	10/56	1	NM_001377530.1	P4

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00193 AC: 480 AN: 249174 Hom.: 1 AF XY: 0.00189 AC XY: 255 AN XY: 135160

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00956

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00221 AC: 3225 AN: 1461574 Hom.: 10 Cov.: 34 AF XY: 0.00209 AC XY: 1521 AN XY: 727072

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.00226

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74468

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00867

Gnomad4 NFE AF: 0.00248

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.000967

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00180 AC: 15

ExAC AF: 0.00186 AC: 225

EpiCase AF: 0.00142

EpiControl AF: 0.000889

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

Apr 24, 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	0.98
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	22
Dann	Pathogenic	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;.;.;D;.;D;D
MetaRNN	Benign	0.0075	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Pathogenic	3.6	H;H;H;H;H;H;H
MutationTaster	Benign	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N;N;D;N;N;D;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Uncertain	0.042	D;T;T;T;D;T;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.27
MVP		0.63
MPC		0.35
ClinPred		0.12	T
GERP RS		4.1
Varity_R		0.56
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs149788698; hg19: chr10-124339217;