10-122570194-C-G

Variant summary

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

The NM_001377530.1(DMBT1):c.124C>G(p.Pro42Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DMBT1 NM_001377530.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.15

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=0.03112787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMBT1	NM_001377530.1	c.124C>G	p.Pro42Ala	missense_variant	3/56	ENST00000338354.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMBT1	ENST00000338354.10	c.124C>G	p.Pro42Ala	missense_variant	3/56	1	NM_001377530.1	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.0010
Dann	Benign	0.17
Eigen	Benign	-2.7
Eigen_PC	Benign	-2.8
FATHMM_MKL	Benign	0.00083	N
LIST_S2	Benign	0.32	T;.;.;T;.;T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.031	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	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.49	N;N;N;N;N;N;.
REVEL	Benign	0.0070
Sift	Benign	0.68	T;T;T;T;T;T;.
Sift4G	Benign	0.094	T;T;T;T;T;T;T
Polyphen		0.030	B;B;B;B;B;B;B
Vest4		0.050
MutPred		0.27		Loss of disorder (P = 0.0763);Loss of disorder (P = 0.0763);Loss of disorder (P = 0.0763);Loss of disorder (P = 0.0763);Loss of disorder (P = 0.0763);Loss of disorder (P = 0.0763);Loss of disorder (P = 0.0763);
MVP		0.12
MPC		0.051
ClinPred		0.086	T
GERP RS		-3.0
Varity_R		0.013
gMVP		0.15

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: rs11523871; hg19: chr10-124329710;