8-22073976-A-T

Variant names:

• chr8-22073976-A-T
• rs4427168
• NM_001387751.1:c.835+141A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387751.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMTN	NM_001387751.1	MANE Select	c.835+141A>T		intron	N/A	NP_001374680.1
	DMTN	NM_001114135.5		c.835+141A>T		intron	N/A	NP_001107607.1
	DMTN	NM_001114136.3		c.835+141A>T		intron	N/A	NP_001107608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMTN	ENST00000358242.6	TSL:5 MANE Select	c.835+141A>T		intron	N/A	ENSP00000350977.3
	DMTN	ENST00000265800.9	TSL:5	c.835+141A>T		intron	N/A	ENSP00000265800.5
	DMTN	ENST00000432128.6	TSL:5	c.835+141A>T		intron	N/A	ENSP00000416111.1

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

African (AFR) AF: 0.460 AC: 5961 AN: 12972

American (AMR) AF: 0.751 AC: 14355 AN: 19122

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 11987 AN: 14482

East Asian (EAS) AF: 0.985 AC: 30777 AN: 31248

South Asian (SAS) AF: 0.816 AC: 39808 AN: 48766

European-Finnish (FIN) AF: 0.787 AC: 27456 AN: 34888

Middle Eastern (MID) AF: 0.814 AC: 2230 AN: 2740

European-Non Finnish (NFE) AF: 0.833 AC: 244324 AN: 293304

Other (OTH) AF: 0.802 AC: 21511 AN: 26820

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

African (AFR) AF: 0.457 AC: 18952 AN: 41490

American (AMR) AF: 0.773 AC: 11804 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.836 AC: 2903 AN: 3472

East Asian (EAS) AF: 0.974 AC: 5045 AN: 5182

South Asian (SAS) AF: 0.817 AC: 3946 AN: 4830

European-Finnish (FIN) AF: 0.779 AC: 8246 AN: 10582

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.831 AC: 56512 AN: 68030

Other (OTH) AF: 0.777 AC: 1640 AN: 2110

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.31
DANN	Benign	0.62
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4427168; hg19: chr8-21931487;