8-22072428-G-T

Variant names:

• chr8-22072428-G-T
• rs201094236
• NM_001387751.1:c.707G>T

Variant summary

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

The NM_001387751.1(DMTN):​c.707G>T​(p.Arg236Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,575,748 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 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: DMTN NM_001387751.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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 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=0.0451459).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMTN	NM_001387751.1	c.707G>T	p.Arg236Leu	missense_variant	Exon 9 of 16	ENST00000358242.6	NP_001374680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMTN	ENST00000358242.6	c.707G>T	p.Arg236Leu	missense_variant	Exon 9 of 16	5	NM_001387751.1	ENSP00000350977.3

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151904 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000144 AC: 28 AN: 194350 Hom.: 0 AF XY: 0.000125 AC XY: 13 AN XY: 103888

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000112

Gnomad NFE exome AF: 0.000279

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000650 AC: 925 AN: 1423844 Hom.: 0 Cov.: 31 AF XY: 0.000608 AC XY: 429 AN XY: 705050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000786

Gnomad4 NFE exome AF: 0.000812

Gnomad4 OTH exome AF: 0.000577

GnomAD4 genome AF: 0.000224 AC: 34 AN: 151904 Hom.: 0 Cov.: 31 AF XY: 0.000243 AC XY: 18 AN XY: 74172

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.707G>T (p.R236L) alteration is located in exon 9 (coding exon 8) of the DMTN gene. This alteration results from a G to T substitution at nucleotide position 707, causing the arginine (R) at amino acid position 236 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.048	.;T;.;.;.;T;T;T;T;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D;.;.;D;D;D;.;.;D;.;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.045	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.60	N;N;.;.;.;.;N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	1.4	N;N;N;N;N;.;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T;T;T;.;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.012	B;B;.;.;.;.;B;B;B;B;B;B
Vest4		0.37
MVP		0.71
MPC		0.38
ClinPred		0.067	T
GERP RS		5.2
Varity_R		0.091
gMVP		0.21

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: rs201094236; hg19: chr8-21929939;