10-122576624-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377530.1(DMBT1):c.509G>A(p.Arg170His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: DMBT1 NM_001377530.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.11

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052728534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMBT1	NM_001377530.1	c.509G>A	p.Arg170His	missense_variant	7/56	ENST00000338354.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMBT1	ENST00000338354.10	c.509G>A	p.Arg170His	missense_variant	7/56	1	NM_001377530.1	P4

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000462 AC: 115 AN: 249088 Hom.: 0 AF XY: 0.000496 AC XY: 67 AN XY: 135132

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.000975

Gnomad NFE exome AF: 0.000594

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000466 AC: 681 AN: 1461526 Hom.: 0 Cov.: 33 AF XY: 0.000475 AC XY: 345 AN XY: 727052

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.000493

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74476

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000486 AC: 2

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.000405 AC: 49

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.509G>A (p.R170H) alteration is located in exon 7 (coding exon 7) of the DMBT1 gene. This alteration results from a G to A substitution at nucleotide position 509, causing the arginine (R) at amino acid position 170 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.74
Dann	Uncertain	0.98
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.69	T;.;.;T;.;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.053	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.36	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	0.35	T
PROVEAN	Benign	-0.030	N;N;N;N;N;N;.
REVEL	Benign	0.013
Sift	Benign	0.15	T;T;T;T;T;T;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T
Polyphen		0.63	P;B;B;B;B;B;B
Vest4		0.20
MVP		0.35
MPC		0.083
ClinPred		0.011	T
GERP RS		-1.2
Varity_R		0.056
gMVP		0.22

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: rs200590365; hg19: chr10-124336140;