8-22073976-A-T

Position:

• chr8-22073976-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001387751.1(DMTN):​c.835+141A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.799 in 636,522 control chromosomes in the GnomAD database, including 207,545 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (42022 hom., cov: 33)
  • Exomes 𝑓: 0.82 (165523 hom.)
• Consequence: DMTN NM_001387751.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.629

Genes affected

DMTN (HGNC:3382): (dematin actin binding protein) The protein encoded by this gene is an actin binding and bundling protein that plays a structural role in erythrocytes, by stabilizing and attaching the spectrin/actin cytoskeleton to the erythrocyte membrane in a phosphorylation-dependent manner. This protein contains a core domain in the N-terminus, and a headpiece domain in the C-terminus that binds F-actin. When purified from erythrocytes, this protein exists as a trimer composed of two 48 kDa polypeptides and a 52 kDa polypeptide. The different subunits arise from alternative splicing in the 3' coding region, where the headpiece domain is located. Disruption of this gene has been correlated with the autosomal dominant Marie Unna hereditary hypotrichosis disease, while loss of heterozygosity of this gene is thought to play a role in prostate cancer progression. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMTN	NM_001387751.1	c.835+141A>T		intron_variant		ENST00000358242.6	NP_001374680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMTN	ENST00000358242.6	c.835+141A>T		intron_variant		5	NM_001387751.1	ENSP00000350977	P1

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110116 AN: 152064 Hom.: 42017 Cov.: 33

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.941

Gnomad AMR AF: 0.773

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.816

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.776

GnomAD4 exome AF: 0.823 AC: 398409 AN: 484342 Hom.: 165523 AF XY: 0.824 AC XY: 211380 AN XY: 256592

Gnomad4 AFR exome AF: 0.460

Gnomad4 AMR exome AF: 0.751

Gnomad4 ASJ exome AF: 0.828

Gnomad4 EAS exome AF: 0.985

Gnomad4 SAS exome AF: 0.816

Gnomad4 FIN exome AF: 0.787

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 0.802

GnomAD4 genome AF: 0.724 AC: 110145 AN: 152180 Hom.: 42022 Cov.: 33 AF XY: 0.726 AC XY: 54010 AN XY: 74396

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.773

Gnomad4 ASJ AF: 0.836

Gnomad4 EAS AF: 0.974

Gnomad4 SAS AF: 0.817

Gnomad4 FIN AF: 0.779

Gnomad4 NFE AF: 0.831

Gnomad4 OTH AF: 0.777

Alfa AF: 0.765 Hom.: 5708

Bravo AF: 0.711

Asia WGS AF: 0.842 AC: 2927 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.31
DANN	Benign	0.62

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: rs4427168; hg19: chr8-21931487;